Broad spectrum 2-(substituted-amino)-benzothiazole sulfonamide hiv protease inhibitors

ABSTRACT

The present invention concerns the compounds having the formula  
                 
 
     N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites thereof, wherein R 1  and R 8  each are H, optionally substituted C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, aryl, Het 1 , Het 2 ; R 1  may also be a radical of formula (R 11a R 11b )NC(R 10a R 10b )CR 9 —; t is 0, 1 or 2; R 2  is H or C 1-6 alkyl; L is —C(═O)—, —O—C(═O)—, —NR 8 —C(═O)—, —O—C 1-6 alkanediyl-C(═O)—, —NR 8 —C 1-6 alkanediyl-C(═O)—, —S(═O) 2 —, —O—S(═O) 2 —, —NR 8 —S(═O) 2 ; R 3  is C 1-6 alkyl, aryl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-4 alkyl, or arylC 1-4 alkyl; R 4  is H, C 1-4 alkylOC(═O), carboxyl, aminoC(═O), mono- or di(C 1-4 alkyl)aminoC(═O), C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or optionally substituted C 1-6 alkyl; A is C 1-6 alkanediyl, —C(═O)—, —C(═S)—, —S(═O) 2 —, C 1-6 alkanediyl-C(═O)—, C 1-6 alkanediyl-C(═S)— or C 1-6 alkanediyl-S(═O) 2 —; R 5  is H, OH, C 1-6 alkyl, Het 1 C 1-6 alkyl, Het 2 C 1-6 alkyl, optionally substituted aminoC 1-6 alkyl; R 6  is C 1-6 alkylO, Het 1 , Het 1 O, Het 2 , Het 2 O, aryl, arylO, C 1-6 alkyloxycarbonylamino or amino; and in case —A— is other than C 1-6 alkanediyl then R 6  may also be C 1-6 alkyl, Het 1 C 1-4 alkyl, Het 1 OC 1-4 alkyl, Het 2 C 1-4 alkyl, Het 2 OC 1-4 alkyl, arylC 1-4 alkyl, arylOC 1-4 alkyl or aminoC 1-4 alkyl; whereby each of the amino groups in the definition of R 6  may optionally be substituted; R 5  and —A—R 6  taken together with the nitrogen atom to which they are attached may also form Het 1  or Het 2 . It further relates to their use as broadspectrum HIV protease inhibitors, processes for their preparation as well as pharmaceutical compositions and diagnostic kits comprising them. It also concerns combinations thereof with another anti-retroviral agent, and to their use in assays as reference compounds or as reagents.

[0001] The present invention relates to2-(substituted-amino)-benzothiazole sulfonamides, their use as asparticprotease inhibitors, in particular as broadspectrum HIV proteaseinhibitors, processes for their preparation as well as pharmaceuticalcompositions and diagnostic kits comprising them. The present inventionalso concerns combinations of the present2-(substituted-amino)-benzothiazole sulfonamides with anotheranti-retroviral agent. It further relates to their use in assays asreference compounds or as reagents.

[0002] The virus causing the acquired immunodeficiency syndrome (AIDS)is known by different names, including T-lymphocyte virus III (HTLV-III)or lymphadenopathy-associated virus (LAV) or AIDS-related virus (ARV) orhuman immunodeficiency virus (HIV). Up until now, two distinct familieshave been identified, i.e. HIV-1 and HIV-2. Hereinafter, HIV will beused to generically denote these viruses.

[0003] One of the critical pathways in a retroviral life cycle is theprocessing of polyprotein precursors by aspartic protease. For instancewith the HIV virus the gag-pol protein is processed by HIV protease. Thecorrect processing of the precursor polyproteins by the asparticprotease is required for the assembly of infectious virions, thus makingthe aspartic protease an attractive target for antiviral therapy. Inparticular for HIV treatment, the HIV protease is an attractive target.

[0004] HIV protease inhibitors (PIs) are commonly administered to AIDSpatients in combination with other anti-HIV compounds such as, forinstance nucleoside reverse transcriptase inhibitors (NRTIs),non-nucleoside reverse transcriptase inhibitors (NNRTIs) or otherprotease inhibitors. Despite the fact that these antiretrovirals arevery useful, they have a common limitation, namely, the targeted enzymesin the HIV virus are able to mutate in such a way that the known drugsbecome less effective, or even ineffective against these mutant HIVviruses. Or, in other words, the HIV virus creates an ever increasingresistance against the available drugs.

[0005] Resistance of retroviruses, and in particular the HIV virus,against inhibitors is a major cause of therapy failure. For instance,half of the patients receiving anti-HIV combination therapy do notrespond fully to the treatment, mainly because of resistance of thevirus to one or more drugs used. Moreover, it has been shown thatresistant virus is carried over to newly infected individuals, resultingin severely limited therapy options for these drug-naive patients.Therefore, there is a need in the art for new compounds for retrovirustherapy, more particularly for AIDS therapy. The need in the art isparticularly acute for compounds that are active not only on wild typeHIV virus, but also on the increasingly more common resistant HIVviruses.

[0006] Known antiretrovirals, often administered in a combinationtherapy regimen, will eventually cause resistance as stated above. Thisoften may force the physician to boost the plasma levels of the activedrugs in order for said antiretrovirals to regain effectivity againstthe mutated HIV viruses. The consequence of which is a highlyundesirable increase in pill burden. Boosting plasma levels may alsolead to an increased risk of non-compliance with the prescribed therapy.Thus, it is not only important to have compounds showing activity for awide range of HIV mutants, it is also important that there is little orno variance in the ratio between activity against mutant HIV virus andactivity against wild type HIV virus (also defined as fold resistance orFR) over a broad range of mutant HIV strains. As such, a patient mayremain on the same combination therapy regimen for a longer period oftime since the chance that a mutant HIV virus will be sensitive to theactive ingredients will be increased.

[0007] Finding compounds with a high potency on the wild type and on awide variety of mutants is also of importance since the pill burden canbe reduced if therapeutic levels are kept to a minimum. One way ofreducing this pill burden is finding anti-HIV compounds with goodbioavailability, i.e. a favorable pharmacokinetic and metabolic profile,such that the daily dose can be minimized and consequently also thenumber of pills to be taken.

[0008] Another important characteristic of a good anti-HIV compound isthat plasma protein binding of the inhibitor has minimal or even noeffect on its potency.

[0009] Thus, there is a high medical need for protease inhibitors thatare able to combat a broad spectrum of mutants of the HIV virus withlittle variance in fold resistance, have a good bioavailability andexperience little or no effect on their potency due to plasma proteinbinding.

[0010] Up until now, several protease inhibitors are on the market orare being developed. One particular core structure (depicted below) hasbeen disclosed in a number of references, such as, WO 95/06030, WO96/22287, WO 96/28418, WO 96/28463, WO 96/28464, WO 96/28465 and WO97/18205. The compounds disclosed therein are described as retroviralprotease inhibitors.

[0011] WO 99/67254 discloses 4-substituted-phenyl sulfonamides capableof inhibiting multi-drug resistant retroviral proteases.

[0012] Surprisingly, the 2-(substituted-amino)-benzothiazolesulfonamides of the present invention are found to have a favorablepharmacological and pharmacokinetic profile. Not only are they activeagainst wild-type HIV virus, but they also show a broadspectrum activityagainst various mutant HIV viruses exhibiting resistance against knownprotease inhibitors.

[0013] Though some of the present 2-(substituted-amino)-benzothiazolesulfonamides appear to fall within the generic description of some ofthe above cited patent publications, they are not specificallydisclosed, suggested or claimed therein, nor would a person skilled inthe art have been motivated to design them as broadspectrum proteaseinhibitors.

[0014] The present invention concerns2-(substituted-amino)-benzothiazole protease inhibitors, having theformula

[0015] and N-oxides, salts, stereoisomeric forms, racemic mixtures,prodrugs, esters and metabolites thereof, wherein

[0016] R₁ and R₈ are, each independently, hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, arylC₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₆alkyl,aryl, Het¹, Het¹C₁₋₆alkyl, Het² or Het²C₁₋₆alkyl;

[0017] R₁ may also be a radical of formula

[0018]  wherein

[0019] R₉, R_(10a) and R_(10b) are, each independently, hydrogen,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl orC₁₋₄alkyl optionally substituted with aryl, Het¹, Het², C₃₋₇cycloalkyl,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, aminosulfonyl, C₁₋₄alkylS(O)_(t), hydroxy,cyano, halogen or amino optionally mono- or disubstituted where thesubstituents are selected from C₁₋₄alkyl, aryl, arylC₁₋₄alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl andHet²C₁₋₄alkyl; whereby R₉, R_(10a) and the carbon atoms to which theyare attached may also form a C₃₋₇cycloalkyl radical; when L is—O—C₁₋₆alkanediyl-C(═O)— or —NR₈—C₁₋₆alkanediyl-C(═O)—, then R9 may alsobe oxo;

[0020] R_(11a) is hydrogen, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl,aryl, arylC₁₋₄alkyl, aminocarbonyl optionally mono- or disubstituted,aminoC₁₋₄alkylcarbonyloxy optionally mono- or disubstituted,C₁₋₄alkyloxycarbonyl, aryloxycarbonyl, Het¹oxycarbonyl, Het²oxycarbonyl,aryloxycarbonylC₁₋₄alkyl, arylC₁₋₄alkyloxycarbonyl, C₁₋₄alkylcarbonyl,C₃₋₇cycloalkylcarbonyl, C₃₋₇cycloalkylC₁₋₄alkyloxycarbonyl,C₃₋₇cycloalkylcarbonyloxy, carboxylC₁₋₄alkylcarbonyloxy,C₁₋₄alkylcarbonyloxy, arylC₁₋₄alkylcarbonyloxy, arylcarbonyloxy,aryloxycarbonyloxy, Het¹carbonyl, Het¹carbonyloxy,Het¹C₁₋₄alkyloxycarbonyl, Het²carbonyloxy, Het²C₁₋₄alkylcarbonyloxy,Het²C₁₋₄alkyloxycarbonyloxy or C₁₋₄alkyl optionally substituted witharyl, aryloxy, Het², halogen or hydroxy; wherein the substituents on theamino groups are each independently selected from C₁₋₄alkyl, aryl,arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het²,Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl;

[0021] R_(11b) is hydrogen, C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,aryl, C₁₋₆alkyloxycarbonyl, Het¹, Het² or C₁₋₄alkyl optionallysubstituted with halogen, hydroxy, C₁₋₄alkylS(═O)_(t), aryl,C₃₋₇cycloalkyl, Het¹, Het², amino optionally mono- or disubstitutedwhere the substituents are selected from C₁₋₄alkyl, aryl, arylC₁₋₄alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl andHet²C₁₋₄alkyl;

[0022] whereby R_(11b) may be linked to the remainder of the moleculevia a sulfonyl group; each independently t is zero, 1 or 2;

[0023] R₂ is hydrogen or C₁₋₆alkyl;

[0024] L is —C(═O)—, —O—C(═O)—, —NR₈—C(═O)—, —O—C₁₋₆alkanediyl-C(═O)—,—NR₈—C₁₋₆-alkanediyl-C(═O)—, —S(═O)₂—, —O—S(═O)₂—, —NR₈—S(═O)₂ wherebyeither the C(═O) group or the S(═O)₂ group is attached to the NR₂moiety; and whereby the alkanediyl moiety is optionally substituted witharyl, arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹,Het², Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl;

[0025] R₃ is C₁₋₆alkyl, aryl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl,or arylC₁₋₄alkyl;

[0026] R₄ is hydrogen, C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl,mono- or di(C₁₋₄alkyl)aminocarbonyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl or C₁₋₆alkyl optionally substituted with aryl, Het¹, Het²,C₃₋₇cycloalkyl, C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, aminosulfonyl, C₁₋₄alkylS(═O)_(t), hydroxy,cyano, halogen or amino optionally mono- or disubstituted where thesubstituents are selected from C₁₋₄alkyl, aryl, aryl-C₁₋₄alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl andHet²C₁₋₄alkyl;

[0027] A is C₁₋₆alkanediyl, —C(═O)—, —C(═S)—, —S(═O)₂—,C₁₋₆alkanediyl-C(═O)—, C₁₋₆alkanediyl-C(═S)— or C₁₋₆alkanediyl-S(═O)₂—;whereby the point of attachment to the nitrogen atom is theC₁₋₆alkanediyl group in those moieties containing said group;

[0028] R₅ is hydrogen, hydroxy, C₁₋₆alkyl, Het¹C₁₋₆alkyl, Het²C₁₋₆alkyl,aminoC₁₋₆alkyl whereby the amino group may optionally be mono- ordi-substituted with C₁₋₄alkyl;

[0029] R₆ is C₁₋₆alkyloxy, Het¹, Het¹oxy, Het², Het²oxy, aryl, aryloxyor amino; and in case —A— is other than C₁₋₆alkanediyl then R⁶ may alsobe C₁₋₆alkyl, Het¹C₁₋₄alkyl, Het¹oxyC₁₋₄alkyl, Het²C₁₋₄alkyl,Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl, aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl;whereby each of the amino groups in the definition of R₆ may optionallybe substituted with one or more substituents selected from C₁₋₄alkyl,C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl, aryl, arylcarbonyl,aryloxycarbonyl, Het¹, Het², arylC₁₋₄alkyl, Het¹C₁₋₄alkyl orHet²C₁₋₄alkyl; and

[0030] R⁵ and —A—R⁶ taken together with the nitrogen atom to which theyare attached may also form Het¹ or Het².

[0031] According to one embodiment, the present invention concerns2-(substituted-amino)-benzothiazole protease inhibitors of formula (I),and N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs,esters and metabolites thereof, wherein

[0032] R₁ and R₈ are, each independently, hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, arylC₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₆alkyl,aryl, Het¹, Het¹C₁₋₆alkyl, Het², Het²C₁₋₆alkyl;

[0033] R₁ may also be a radical of formula

[0034]  wherein

[0035] R₉, R_(10a) and R_(10b) are, each independently, hydrogen,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl orC₁₋₄alkyl optionally substituted with aryl, Het¹, Het², C₃₋₇cycloalkyl,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, aminosulfonyl, C₁₋₄alkylS(O)_(t), hydroxy,cyano, halogen or amino optionally mono- or disubstituted where thesubstituents are selected from C₁₋₄alkyl, aryl, arylC₁₋₄alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl andHet²C₁₋₄alkyl; whereby R₉, R_(10a) and the carbon atoms to which theyare attached may also form a C₃₋₇cycloalkyl radical;

[0036] R_(11a) is hydrogen, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl,aryl, aminocarbonyl optionally mono- or disubstituted,aminoC₁₋₄alkylcarbonyloxy optionally mono- or disubstituted,C₁₋₄alkyloxycarbonyl, aryloxycarbonyl, Het¹oxycarbonyl, Het²oxycarbonyl,aryloxycarbonylC₁₋₄alkyl, arylC₁₋₄alkyloxycarbonyl, C₁₋₄alkylcarbonyl,C₃₋₇cycloalkylcarbonyl, C₃₋₇cycloalkylC₁₋₄alkyloxycarbonyl,C₃₋₇cycloalkylcarbonyloxy, carboxylC₁₋₄alkylcarbonyloxy,C₁₋₄alkylcarbonyloxy, arylC₁₋₄alkylcarbonyloxy, arylcarbonyloxy,aryloxycarbonyloxy, Het¹carbonyl, Het¹carbonyloxy,Het¹C₁₋₄alkyloxycarbonyl, Het²carbonyloxy, Het²C₁₋₄alkylcarbonyloxy,Het²C₁₋₄alkyloxycarbonyloxy or C₁₋₄alkyl optionally substituted witharyl, aryloxy, Het² or hydroxy; wherein the substituents on the aminogroups are each independently selected from C₁₋₄alkyl, aryl,arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het²,Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl;

[0037] R_(11b) is hydrogen, C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,aryl, Het¹, Het² or C₁₋₄alkyl optionally substituted with halogen,hydroxy, C₁₋₄alkylS(═O)_(t), aryl, C₃₋₇cycloalkyl, Het¹, Het², aminooptionally mono- or disubstituted where the substituents are selectedfrom C₁₋₄alkyl, aryl, arylC₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl;

[0038]  whereby R_(11b) may be linked to the remainder of the moleculevia a sulfonyl group; each independently t is zero, 1 or 2;

[0039] R₂ is hydrogen or C₁₋₆alkyl;

[0040] L is —C(═O)—, —O—C(═O)—, —NR₈—C(═O)—, —O—C₁₋₆alkanediyl-C(═O)—,—NR₈—C₁₋₆alkanediyl-C(═O)—, —S(═O)₂—, —O—S(═O)₂—, —NR₈—S(═O)₂ wherebyeither the C(═O) group or the S(═O)₂ group is attached to the NR₂moiety;

[0041] R₃ is C₁₋₆alkyl, aryl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl,or arylC₁₋₄alkyl;

[0042] R₄ is hydrogen, C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl,mono- or di(C₁₋₄alkyl)aminocarbonyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl or C₁₋₆alkyl optionally substituted with aryl, Het¹, Het²,C₃₋₇cycloalkyl, C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, aminosulfonyl, C₁₋₄alkylS(═O)_(t), hydroxy,cyano, halogen or amino optionally mono- or disubstituted where thesubstituents are selected from C₁₋₄alkyl, aryl, arylC₁₋₄alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl andHet²C₁₋₄alkyl;

[0043] A is C₁₋₆alkanediyl, —C(═O)—, —C(═S)—, —S(═O)₂—,C₁₋₆alkanediyl-C(═O)—, C₁₋₆alkanediyl-C(═S)— or C₁₋₆alkanediyl-S(═O)₂—;whereby the point of attachment to the nitrogen atom is theC₁₋₆alkanediyl group in those moieties containing said group;

[0044] R₅ is hydrogen, hydroxy, C₁₋₆alkyl, Het¹C₁₋₆alkyl, Het²C₁₋₆alkyl,aminoC₁₋₆alkyl whereby the amino group may optionally be mono- ordi-substituted with C₁₋₄alkyl;

[0045] R₆ is C₁₋₆alkyloxy, Het¹, Het¹oxy, Het², Het²oxy, aryl, aryloxyor amino; and in case —A— is other than C₁₋₆alkanediyl then R⁶ may alsobe C₁₋₆alkyl, Het¹C₁₋₄alkyl, Het¹oxyC₁₋₄alkyl, Het²C₁₋₄alkyl,Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl, aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl;whereby each of the amino groups in the definition of R₆ may optionallybe substituted with one or more substituents selected from C₁₋₄alkyl,C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl, aryl, arylcarbonyl,aryloxycarbonyl, Het¹, Het², arylC₁₋₄alkyl, Het C₁₋₄alkyl orHet²C₁₋₄alkyl; and

[0046] R₅ and —A—R₆ taken together with the nitrogen atom to which theyare attached may also form Het¹ or Het².

[0047] This invention also envisions the quaternization of the nitrogenatoms of the present compounds. A basic nitrogen can be quaternized withany agent known to those of ordinary skill in the art including, forinstance, lower alkyl halides, dialkyl sulfates, long chain halides andaralkyl halides.

[0048] Whenever the term “substituted” is used in defining the compoundsof formula (I), it is meant to indicate that one or more hydrogens onthe atom indicated in the expression using “substituted” is replacedwith a selection from the indicated group, provided that the indicatedatom's normal valency is not exceeded, and that the substitution resultsin a chemically stable compound, i.e. a compound that is sufficientlyrobust to survive isolation to a useful degree of purity from a reactionmixture, and formulation into a therapeutic agent.

[0049] As used herein, the term “halo” or “halogen” as a group or partof a group is generic for fluoro, chloro, bromo or iodo.

[0050] The term “C₁₋₄alkyl” as a group or part of a group definesstraight and branched chained saturated hydrocarbon radicals having from1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyland 2-methyl-propyl, the like.

[0051] The term “C₁₋₆alkyl” as a group or part of a group definesstraight and branched chained saturated hydrocarbon radicals having from1 to 6 carbon atoms such as the groups defined for C₁₋₄alkyl and pentyl,hexyl, 2-methylbutyl, 3-methylpentyl and the like.

[0052] The term “C₁₋₆alkanediyl” as a group or part of a group definesbivalent straight and branched chained saturated hydrocarbon radicalshaving from 1 to 6 carbon atoms such as, for example, methylene,ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl,pentan-1,5-diyl, hexan-1,6-diyl, 2-methylbutan-1,4-diyl,3-methylpentan-1,5-diyl and the like.

[0053] The term “C₂₋₆alkenyl” as a group or part of a group definesstraight and branched chained hydrocarbon radicals having from 2 to 6carbon atoms containing at least one double bond such as, for example,ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.

[0054] The term “C₂₋₆alkynyl” as a group or part of a group definesstraight and branched chained hydrocarbon radicals having from 2 to 6carbon atoms containing at least one triple bond such as, for example,ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.

[0055] The term “C₃₋₇cycloalkyl” as a group or part of a group isgeneric to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl.

[0056] The term “aryl” as a group or part of a group is meant to includephenyl and naphtyl which both may be optionally substituted with one ormore substituents independently selected from C₁₋₆alkyl, C₁₋₆alkyloxy,halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano,haloC₁₋₆alkyl, carboxyl, C₁₋₆alkoxycarbonyl, C₃₋₇cycloalkyl, Het¹,optionally mono- or disubstituted aminocarbonyl, optionally mono- ordisubstituted aminoC₁₋₆alkyl, methylthio, methylsulfonyl, and phenyloptionally substituted with one or more substituents selected fromC₁₋₆alkyl, C₁₋₆alkyloxy, halogen, hydroxy, optionally mono- ordisubstituted amino, nitro, cyano, haloC₁₋₆alkyl, carboxyl,C₁₋₆alkoxycarbonyl, C₃₋₇cycloalkyl, Het¹, optionally mono- ordisubstituted aminocarbonyl, methylthio and methylsulfonyl; whereby theoptional substituents on any amino function are independently selectedfrom C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy-A—, Het¹-A—,Het¹C₁₋₆alkyl, Het¹C₁₋₆alkyl-A—, Het¹oxy-A—, Het¹oxyC₁₋₄akyl-A—,phenyl-A—, phenyl-oxy-A—, phenyloxyC₁₋₄alkyl-A—, phenylC₁₋₆alkyl-A—,C₁₋₆alkyloxycarbonylamino-A—, amino-A—, aminoC₁₋₆alkyl andaminoC₁₋₆alkyl-A— whereby each of the amino groups may optionally bemono- or where possible di-substituted with C₁₋₄alkyl and whereby A isas defined above.

[0057] The term “haloC₁₋₆alkyl” as a group or part of a group is definedas C₁₋₆alkyl substituted with one or more halogen atoms, preferably,chloro or fluoro atoms, more preferably fluoro atoms. PreferredhaloC₁₋₆alkyl groups include for instance trifluoromethyl anddifluoromethyl.

[0058] The term “Het¹” as a group or part of a group is defined as asaturated or partially unsaturated monocyclic, bicyclic or tricyclicheterocycle having preferably 3 to 14 ring members, more preferably 5 to10 ring members and more preferably 5 to 8 ring members, which containsone or more heteroatom ring members selected from nitrogen, oxygen orsulfur and which is optionally substituted on one or more carbon atomsby C₁₋₆alkyl, C₁₋₆alkyloxy, halogen, hydroxy, oxo, optionally mono- ordisubstituted amino, nitro, cyano, haloC₁₋₆alkyl, carboxyl,C₁₋₆alkoxycarbonyl, C₃₋₇cycloalkyl, optionally mono- or disubstitutedaminocarbonyl, optionally mono- or disubstituted aminoC₁₋₆alkyl,methylthio, methylsulfonyl, aryl and a saturated or partiallyunsaturated monocyclic, bicyclic or tricyclic heterocycle having 3 to 14ring members which contains one or more heteroatom ring members selectedfrom nitrogen, oxygen or sulfur and whereby the optional substituents onany amino function are independently selected from C₁₋₆alkyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy-A—, Het²—A—, Het²C₁₋₆alkyl,Het²C₁₋₆alkyl-A—, Het²oxy-A—, Het²oxyC₁₋₄akyl-A—, aryl-A—, aryloxy-A—,aryloxyC₁₋₄alkyl-A—, arylC₁₋₆alkyl-A—, C₁₋₆alkyloxycarbonylamino-A—,amino-A—, aminoC₁₋₆alkyl and aminoC₁₋₆alkyl-A— whereby each of the aminogroups may optionally be mono- or where possible di-substituted withC₁₋₄alkyl and whereby A is as defined above.

[0059] The term “Het²” as a group or part of a group is defined as anaromatic monocyclic, bicyclic or tricyclic heterocycle having preferably3 to 14 ring members, more preferably 5 to 10 ring members and morepreferably 5 to 6 ring members, which contains one or more heteroatomring members selected from nitrogen, oxygen or sulfur and which isoptionally substituted on one or more carbon atoms by C₁₋₆alkyl,C₁₋₆alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino,nitro, cyano, haloC₁₋₆alkyl, carboxyl, C₁₋₆alkoxycarbonyl,C₃₋₇cycloalkyl, optionally mono- or disubstituted aminocarbonyl,optionally mono- or disubstituted aminoC₁₋₆alkyl, methylthio,methylsulfonyl, aryl, Het¹ and an aromatic monocyclic, bicyclic ortricyclic heterocycle having 3 to 14 ring members; whereby the optionalsubstituents on any amino function are independently selected fromC₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy-A—, Het¹-A—, Het¹C₁₋₆alkyl,Het¹C₁₋₆alkyl-A—, Het¹oxy-A—, Het¹oxyC₁₋₄akyl-A—, aryl-A—, aryloxy-A—,aryloxyC₁₋₄alkyl-A—, arylC₁₋₆alkyl-A—, C₁₋₆alkyloxycarbonylamino-A—,amino-A—, aminoC₁₋₆alkyl and aminoC₁₋₆alkyl-A— whereby each of the aminogroups may optionally be mono- or where possible di-substituted withC₁₋₄alkyl and whereby A is as defined above.

[0060] As used herein, the term (═O) forms a carbonyl moiety with thecarbon atom to which it is attached.

[0061] As used herein before, the term “one or more” covers thepossibility of all the available C-atoms, where appropriate, to besubstituted, preferably, one, two or three.

[0062] When any variable (e.g. halogen or C₁₋₄alkyl) occurs more thanone time in any constituent, each definition is independent.

[0063] The term “prodrug” as used throughout this text means thepharmacologically acceptable derivatives such as esters, amides andphosphates, such that the resulting in vivo biotransformation product ofthe derivative is the active drug as defined in the compounds of formula(I). The reference by Goodman and Gilman (The Pharmacological Basis ofTherapeutics, 8^(th) ed, McGraw-Hill, Int. Ed. 1992, “Biotransformationof Drugs”, p 13-15) describing prodrugs generally is herebyincorporated. Prodrugs of a compound of the present invention areprepared by modifying functional groups present in the compound in sucha way that the modifications are cleaved, either in routine manipulationor in vivo, to the parent compound. Prodrugs include compounds of thepresent invention wherein a hydroxy group, for instance the hydroxygroup on the asymmetric carbon atom, or an amino group is bonded to anygroup that, when the prodrug is administered to a patient, cleaves toform a free hydroxyl or free amino, respectively.

[0064] Typical examples of prodrugs are described for instance in WO99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 all incorporatedherein by reference.

[0065] Prodrugs are characterized by excellent aqueous solubility,increased bioavailability and are readily metabolized into the activeinhibitors in vivo.

[0066] For therapeutic use, the salts of the compounds of formula (I)are those wherein the counterion is pharmaceutically or physiologicallyacceptable. However, salts having a pharmaceutically unacceptablecounterion may also find use, for example, in the preparation orpurification of a pharmaceutically acceptable compound of formula (I).All salts, whether pharmaceutically acceptable or not are includedwithin the ambit of the present invention.

[0067] The pharmaceutically acceptable or physiologically tolerableaddition salt forms which the compounds of the present invention areable to form can conveniently be prepared using the appropriate acids,such as, for example, inorganic acids such as hydrohalic acids, e.g.hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and thelike acids; or organic acids such as, for example, acetic, propanoic,hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic,fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-amino-salicylic, pamoic and the like acids.

[0068] Conversely said acid addition salt forms can be converted bytreatment with an appropriate base into the free base form.

[0069] The compounds of formula (I) containing an acidic proton may alsobe converted into their non-toxic metal or amine addition salt form bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.the benzathine, N-methyl, -D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

[0070] Conversely said base addition salt forms can be converted bytreatment with an appropriate acid into the free acid form.

[0071] The term “salts” also comprises the hydrates and the solventaddition forms which the compounds of the present invention are able toform. Examples of such forms are e.g. hydrates, alcoholates and thelike.

[0072] The N-oxide forms of the present compounds are meant to comprisethe compounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

[0073] The present compounds may also exist in their tautomeric forms.Such forms, although not explicitly indicated in the above formula areintended to be included within the scope of the present invention.

[0074] The term stereochemically isomeric forms of compounds of thepresent invention, as used hereinbefore, defines all possible compoundsmade up of the same atoms bonded by the same sequence of bonds buthaving different three-dimensional structures which are notinterchangeable, which the compounds of the present invention maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of a compound encompasses the mixture of all possiblestereochemically isomeric forms which said compound may possess. Saidmixture may contain all diastereomers and/or enantiomers of the basicmolecular structure of said compound. All stereochemically isomericforms of the compounds of the present invention both in pure form or inadmixture with each other are intended to be embraced within the scopeof the present invention.

[0075] Pure stereoisomeric forms of the compounds and intermediates asmentioned herein are defined as isomers substantially free of otherenantiomeric or diastereomeric forms of the same basic molecularstructure of said compounds or intermediates. In particular, the term‘stereoisomerically pure’ concerns compounds or intermediates having astereoisomeric excess of at least 80% (i. e. minimum 90% of one isomerand maximum 10% of the other possible isomers) up to a stereoisomericexcess of 100% (i.e. 100% of one isomer and none of the other), more inparticular, compounds or intermediates having a stereoisomeric excess of90% up to 100%, even more in particular having a stereoisomeric excessof 94% up to 100% and most in particular having a stereoisomeric excessof 97% up to 100%. The terms ‘enantiomerically pure’ and‘diastereomerically pure’ should be understood in a similar way, butthen having regard to the enantiomeric excess, respectively thediastereomeric excess of the mixture in question.

[0076] Pure stereoisomeric forms of the compounds and intermediates ofthis invention may be obtained by the application of art-knownprocedures. For instance, enantiomers may be separated from each otherby the selective crystallization of their diastereomeric salts withoptically active acids. Alternatively, enantiomers may be separated bychromatographic techniques using chiral stationary phases. Said purestereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably, if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

[0077] The diastereomeric racemates of formula (I) can be obtainedseparately by conventional methods. Appropriate physical separationmethods which may advantageously be employed are, for example, selectivecrystallization and chromatography, e.g. column chromatography.

[0078] It is clear to a person skilled in the art that the compounds offormula (I) contain at least one asymmetric center and thus may exist asdifferent stereoisomeric forms. This asymmetric center is indicated witha asterisk (*) in the figure below.

[0079] The absolute configuration of each asymmetric center that may bepresent in the compounds of formula (I) may be indicated by thestereochemical descriptors R and S, this R and S notation correspondingto the rules described in Pure Appl. Chem. 1976, 45, 11-30. The carbonatom marked with the asterisk (*) preferably has the R configuration.

[0080] The present invention is also intended to include all isotopes ofatoms occurring on the present compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. By way ofgeneral example and without limitation, isotopes of hydrogen includetritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0081] Whenever used hereinafter, the term “compounds of formula (I)”,or “the present compounds” or similar term is meant to include thecompounds of general formula (I), their N-oxides, salts, stereoisomericforms, racemic mixtures, prodrugs, esters and metabolites, as well astheir quaternized nitrogen analogues.

[0082] A particular group of compounds are those compounds of formula(I) wherein one or more of the following restrictions apply:

[0083] R₁ is hydrogen, Het¹, Het², aryl, Het¹C₁₋₆alkyl, Het²C₁₋₆alkyl,arylC₁₋₆alkyl, more in particular, R₁ is hydrogen, a saturated orpartially unsaturated monocyclic or bicyclic heterocycle having 5 to 8ring members, which contains one or more heteroatom ring membersselected from nitrogen, oxygen or sulfur and which is optionallysubstituted, phenyl optionally substituted with one or moresubstituents, an aromatic monocyclic heterocycle having 5 to 6 ringmembers, which contains one or more heteroatom ring members selectedfrom nitrogen, oxygen or sulfur and which is optionally substituted onone or more carbon atoms, or C₁₋₆alkyl substituted with an aromaticmonocyclic heterocycle having 5 to 6 ring members, which contains one ormore heteroatom ring members selected from nitrogen, oxygen or sulfurand which is optionally substituted on one or more carbon atoms;

[0084] R_(11a) is H, alkyloxycarbonyl;,

[0085] R_(11b) is C₁₋₄ alkyl optionally substituted with aryl;

[0086] R₂ is hydrogen;

[0087] L is —C(═O)—, —O—C(═O)—, —O—C₁₋₆alkanediyl-C(═O)—,—NR₈—C₁₋₆alkanediyl-C(═O), more in particular, L is —C(═O)—, —O—C(═O)—,—O—CH₂—C(═O)—, whereby in each case the C(═O) group is attached to theNR₂ moiety;

[0088] R₃ is arylC₁₋₄alkyl, in particular, arylmethyl, more inparticular phenylmethyl;

[0089] R₄ is optionally substituted C₁₋₆alkyl, in particular C₁₋₆alkyloptionally substituted with aryl, Het¹, Het², C₃₋₇cycloalkyl or aminooptionally mono- or disubstituted where the substituents are selectedfrom C₁₋₄alkyl, aryl, Het¹ and Het²;

[0090] A is C₁₋₆alkanediyl, —C(═O)— or C₁₋₆alkanediyl-C(═O)—, inparticular, A is methylene, 1,2-ethanediyl, 1,3-propanediyl, —C(═O)— or—CH₂—C(═O)—;

[0091] R₅ is hydrogen, C₁₋₆alkyl, Het¹C₁₋₆alkyl, aminoC₁₋₆alkyl wherebythe amino group may optionally be mono- or di-substituted withC₁₋₄alkyl;

[0092] R₆ is C₁₋₆alkyloxy, Het¹, aryl, amino; and in case —A— is otherthan C₁₋₆alkanediyl then R₆ may also be C₁₋₆alkyl, Het¹C₁₋₄alkyl,aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl; whereby each of the amino groups mayoptionally be substituted; or

[0093] R₅ and —A—R₆ taken together with the nitrogen atom to which theyare attached may also form Het¹.

[0094] A special group of compounds are those compounds of formula (I)wherein R₁ is Het¹, aryl, Het²C₁₋₆alkyl; R₂ is hydrogen; L is —C(═O)—,—O—C(═O)—, —O—CH₂—C(═O)—, whereby in each case the C(═O) group isattached to the NR₂ moiety; R₃ is phenylmethyl; and R₄ is C₁₋₆alkyl.

[0095] Also a special group of compounds are those compounds of formula(I) wherein A is C₁₋₆alkanediyl or —C(═O)—; R₅ is hydrogen, methyl,Het¹C₁₋₆alkyl, aminoC₁₋₆alkyl whereby the amino group may optionally bemono- or di-substituted with C₁₋₄alkyl; R₆ is C₁₋₆alkyloxy, Het¹, amino;and in case —A— is other than C₁₋₆alkanediyl then R⁶ may also beC₁₋₆alkyl, Het¹C₁₋₄alkyl or aminoC₁₋₄alkyl; whereby each of the aminogroups may optionally be substituted.

[0096] An interesting group of compounds are those compounds of formula(I) wherein —A— is carbonyl and R₆ is aryl, Het¹C₁₋₄alkyl,aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl, whereby the amino groups mayoptionally be substituted; or —A— is carbonyl, R₆ is C₁₋₄alkyl and R₅ isHet¹C₁₋₆alkyl or aminoC₁₋₆alkyl whereby the amino group may optionallybe mono- or di-substituted with C₁₋₄alkyl.

[0097] Another interesting group of compounds are those compounds offormula (I) wherein —A— is C₁₋₆alkanediyl and R₆ is amino and Het¹;whereby the amino group may optionally be mono- or di-substituted withC₁₋₄alkyl.

[0098] Another interesting group of compounds are those compounds offormula (I) wherein R₁ hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, arylC₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₆alkyl, aryl, Het¹, Het¹C₁₋₆alkyl,Het², Het²C₁₋₆alkyl; wherein Het¹ is a saturated or partiallyunsaturated monocyclic heterocycle having 5 or 6 ring members, whichcontains one or more heteroatom ring members selected from nitrogen,oxygen or sulfur and which is optionally substituted on one or morecarbon atoms.

[0099] Another interesting group of compounds are those compounds offormula (I) wherein L is —O—C₁₋₆alkanediyl-C(═O)—.

[0100] Another interesting group of compounds are those compounds offormula (I) wherein

[0101] A is C₁₋₆alkanediyl, —C(═O)— or C₁₋₆alkanediyl-C(═O)—; wherebythe point of attachment to the nitrogen atom is the C₁₋₆alkanediyl groupin those moieties containing said group;

[0102] R₅ is hydrogen, C₁₋₆alkyl, Het¹C₁₋₆alkyl, Het²C₁₋₆alkyl,aminoC₁₋₆alkyl whereby the amino group may optionally be mono- ordi-substituted with C₁₋₄alkyl; and

[0103] in case —A— is —C(═O)— then R⁶ is C₁₋₆alkyloxy, Het¹, Het¹oxy orHet²oxy, aryl, Het¹C₁₋₄alkyl, Het¹oxyC₁₋₄alkyl, Het²C₁₋₄alkyl,Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl, aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl; and

[0104] in case —A— is C₁₋₆alkanediyl then R⁶ is amino, C₁₋₆alkyloxy,Het¹, Het¹oxy or Het²oxy; and

[0105] in case —A— is C₁₋₆alkanediyl-C(═O)— then R⁶ is C₁₋₆alkyloxy,Het¹, Het¹oxy or Het²oxy, aryl, C₁₋₆alkyl, Het¹C₁₋₄alkyl,Het¹oxyC₁₋₄alkyl, Het²C₁₋₄alkyl, Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl,aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl;

[0106] whereby each of the amino groups in the definition of R₆ mayoptionally be substituted with one or more substituents selected fromC₁₋₄alkyl, C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl, aryl, arylcarbonyl,aryloxycarbonyl, Het¹, Het², arylC₁₋₄alkyl, Het¹C₁₋₄alkyl orHet²C₁₋₄alkyl; and

[0107] R₅ and —A—R⁶ taken together with the nitrogen atom to which theyare attached may also form Het¹ whereby Het¹ is substituted by at leastan oxo group.

[0108] Interesting compounds are those wherein L is—O—C₁₋₆alkanediyl-C(═O)— or —NR₈—C₁₋₆-alkanediyl-C(═O)— and R₁ is aradical of formula

[0109] wherein

[0110] R₉ is oxo;

[0111] R_(10a) and R_(10b) are, each independently, hydrogen orC₁₋₄alkyl optionally substituted with aryl, Het¹, Het²,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, hydroxy, or aminooptionally mono- or disubstituted where the substituents are selectedfrom C₁₋₄alkyl,

[0112] R_(11a) is arylC₁₋₄alkyl, or C₁₋₄alkyl optionally substitutedwith aryl or halogen and

[0113] R_(11b) is hydrogen, or C₁₋₆alkyloxycarbonyl.

[0114] Also interesting compounds are those wherein L is—O—C₁₋₆alkanediyl-C(═O)— or —NR₈—C₁₋₆alkanediyl-C(═O)— and R₁ is aradical of formula

[0115] wherein

[0116] R₉ is oxo,

[0117] R_(10a) and R_(10b) are hydrogen,

[0118] R_(11a) is arylC₁₋₄alkyl wherein the aryl group is substitutedwith a halogen and

[0119] R_(11b) is hydrogen, or C₁₋₆alkyloxycarbonyl.

[0120] Other interesting compounds are those wherein L is—O—C₁₋₆alkanediyl-C(═O)— or —NR₈—C₁₋₆alkanediyl-C(═O)— and R₁ is aradical of formula

[0121] wherein R₉ is oxo, R_(10a) and R_(10b) are hydrogen, R_(11a) ism-fluorobenzyl and R_(11b) is hydrogen, or C₁₋₆alkyloxycarbonyl.

[0122] Yet other interesting compounds are those wherein L is—O—C₁₋₆alkanediyl-C(═O)— or —NR₈—C₁₋₆alkanediyl-C(═O)— and R₁ is aradical of formula

[0123] wherein R₉ is oxo, R_(10a) and R_(10b) are hydrogen, R_(11a) ism-fluorobenzyl and R_(11b) is hydrogen.

[0124] Other interesting compounds are those wherein L is—O—C₁₋₆alkanediyl-C(═O)— or —NR₈—C₁₋₆alkanediyl-C(═O)— and R₁ is aradical of formula

[0125] wherein R₉ is oxo, R_(10a) and R_(10b) are hydrogen, R_(11a) ism-fluorobenzyl and R_(11b) is tert-butyloxycarbonyl.

[0126] Interestingly, the compounds of the present invention maycomprise chemically reactive moieties capable of forming covalent bondsto localized sites such that said compound have increased tissueretention and half-lives. The term “chemically reactive group” as usedherein refers to chemical groups capable of forming a covalent bond.Reactive groups will generally be stable in an aqueous environment andwill usually be carboxy, phosphoryl, or convenient acyl group, either asan ester or a mixed anhydride, or an imidate, or a maleimidate therebycapable of forming a covalent bond with functionalities such as an aminogroup, a hydroxy or a thiol at the target site on for example bloodcomponents.

[0127] Upon administration to an individual in need thereof, saidcompound is capable of forming covalent bonds to localized sites, withblood component for example, such that said compound according to theinvention has increased tissue retention and half-lives. Usually, thecovalent bond that is formed should be able to be maintained during thelifetime of the blood component, unless it is intended to be a releasesite. A major advantage of said new compound is the small amount ofcompound necessary to provide an effective effect. The reasons for thisadvantage are explained by the targeting of the delivery, the high yieldof reaction between the reactive entity Y and reactive functionality andthe irreversible nature of the bond formed after reaction. Furthermore,once bound to the membrane or tissue said compound according to theinvention is not susceptible to liver metabolism, kidney filtration andexcretion, and may even be protected from protease (inclusive ofendopeptidase) activity which usually leads to loss of activity andaccelerated elimination.

[0128] “Blood components” as used herein refers to either fixed ormobile blood components. Fixed blood components are non-mobile bloodcomponents and include tissues, membrane receptors, interstitialproteins, fibrin proteins, collagens, platelets, endothelial cells,epithelial cells and their associated membrane and membranous receptors,somatic body cells, skeletal and smooth muscle cells, neuronalcomponents, osteocytes and osteoclasts and all body tissues especiallythose associated with the circulatory and lymphatic systems. Mobileblood components are blood components that do not have a fixed situs forany extended period of time, generally not exceeding 5, more usually oneminute. These blood components are not membrane-associated and arepresent in the blood for extended periods of time and are present in aminimum concentration of at least 0.1 μg/ml. Mobile blood componentsinclude serum albumin, transferrin, ferritin and immunoglobulins such asIgM and IgG. The half-life of mobile blood components is at least about12 hours.

[0129] The compounds of formula (I) can generally be prepared usingprocedures analogous to those procedures described in WO 95/06030, WO96/22287, WO 96/28418, WO 96/28463, WO 96/28464, WO 96/28465 and WO97/18205.

[0130] Particular reaction procedures to make the present compounds aredescribed below. In the preparations described below, the reactionproducts may be isolated from the medium and, if necessary, furtherpurified according to methodologies generally known in the art such as,for example, extraction, crystallization, trituration andchromatography.

[0131] The 2-acetamido-6-chlorosulfonylbenzothiazole (intermediate a-2)was prepared following the procedure described in EP-A-0,445,926.Intermediates a-4 were prepared by reacting an intermediate a-3,prepared according to the procedure described in WO97/18205 and alsodepicted in scheme F, with an intermediate a-2 in a reaction-inertsolvent such as dichloromethane, and in the presence of a base such astriethylamine and at low temperature, for example at 0° C. The Boc groupin the intermediate a-3 is a protective tert-butyloxycarbonyl group. Itmay conveniently be replaced by another suitable protective group suchas phtalimido or benzyloxycarbonyl. Using intermediate a-4 as a startingmaterial, intermediate a-5 was deprotected using an acid such astrifluoroacetic acid in a suitable solvent such as dicloromethane. Theresulting intermediate may be further reacted with an intermediate offormula R₁—L-(leaving group) in the presence of a base such astriethylamine and optionally in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloric acid (EDC) oran alcohol such as tert-butanol, and in a suitable solvent such asdichloromethane; thus forming intermediates a-6. Particularly,intermediates of formula R₁—C(═O)—OH are suitable to further react withan intermediate a-5.

[0132] Alternatively, intermediates a-4 may be deprotected with a strongacid such as hydrochloric acid in isopropanol, in a suitable solventsuch as a mixture of ethanol and dioxane, thus preparing an intermediatea-7. Intermediates a-8 can be prepared analogously to the proceduredescribed for the preparation of intermediates a-6.

[0133] Intermediate b-5 can be prepared according to the proceduredescribed in scheme A. The aminobenzothiazole derivative b-5 can bede-aminated by for instance treatment with sodium nitrite in combinationwith phosphoric acid, and subsequently with copper sulphate and sodiumchloride, thus obtaining an intermediate b-6. Intermediate b-6 may thenbe reacted with an intermediate of formula R₁—L-(leaving group) in thepresence of a base such as triethylamine and optionally in the presenceof EDC or an alcohol such as t-butanol, and in a suitable solvent suchas dichloromethane, thus obtaining an intermediate b-8. Intermediate b-8may further be derivatized with an amine of formula H₂N-—A—R₆ in asuitable solvent such as acetonitrile to obtain an intermediate b-9.Alternatively, intermediates b-6 may first be reacted with H₂N—A—R₆ andthen with formula R₁—L-(leaving group) as is shown in scheme B.Intermediate b-9 can finally be further reacted with R₅COCl or afunctional equivalent thereof in the presence of a base such astriethylamine and in a suitable solvent such as dichloromethane.Conveniently, said reaction is carried out under an inert atmosphere.

[0134] An alternative way of preparing compounds of formula (I) isexemplified in scheme C. Intermediate c-1, prepared according to theprocedure described in U.S. Pat. No. 6,140,505, was reacted withthiocarbonyldiimidazole in a reaction inert solvent such astetrahydrofuran, and the resulting intermediate was further reacted withan amine such as for instance dimethylethylamine, thus obtaining thethiourea derivative c-2. Said intermediate c-2 was then cyclized withbromine in the presence of an acid such as acetic acid, thus obtaining abenzthiazole derivative c-3. The following two steps in scheme C areanalogous as those described for the preparation of intermediates a-5and a-6 in scheme A. If so desired, intermediate c-5 can be N-oxidizedusing for example meta chloroperbenzoic acid in dichloromethane.

[0135] A particular way of preparing acetamide substitutedbenzothiazoles is depicted in scheme D.

[0136] Intermediate d-1, prepared following the procedure as describedin Scheme A, may be reacted with chloroacetylchloride, or a functionalanalogue, in the presence of a base such as triethiylamine and in asolvent such as 1,4-dioxane in order to obtain an amide of formula d-2.Said intermediate d-2 can further be reacted with an amine of formulaNRaRb whereby Ra and Rb are defined as the possible substituents on anamino group in the variable R₆.

[0137] Another particular way of preparing acetamide substitutedbenzothiazoles is depicted in scheme E.

[0138] Intermediate e-2 can be prepared by treating intermediate e-1,prepared following the procedure described in scheme A, with a base suchas sodiumcarbonate in an aqueous medium such as a water dioxane mixture.The synthesis steps depicted in scheme E to obtain intermediate e-6 areall analogous to reaction procedures described in the above synthesisschemes.

[0139] A number of intermediates and starting materials used in theforegoing preparations are known compounds, while others may be preparedaccording to art-known methodologies of preparing said or similarcompounds.

[0140] Intermediate f-2, corresponding to intermediate a-3 in scheme A,may be prepared by adding an amine of formula H₂N—R₄ to an intermediatef-1 in a suitable solvent such as isopropanol.

[0141] The compounds according to the present invention may also beprepared according to the method as depicted in scheme G.

[0142] The benzothiazole derivative g-1 may be reacted withchlorosulfonic acid and subsequently treated with thionylchloride toyield intermediate g-2. Said intermediate g-2 may be further reactedwith intermediate g-3 yielding an intermediate g-4 wherein PG means asuitable protecting group such as for example Boc,. Said reaction may beperformed in a suitable solvent such as for example2-methyltetrahydrofuran and optionally in the presence of a suitablebase such as triethylamine,

[0143] The intermediate g-4 may then be reacted with a suitable reagentsuch as meta-chloroperoxybenzoic acid (mCPBA) or magnesiummonoperoxyphtalate hexahydrate (MMPP) in the presence of a suitablesolvent such as 2-methyltetrahydrofuran in ethanol thereby producingintermediates g-5 and g-6.

[0144] Intermediates g-5 and g-6 may be further derivatized with acompound of formula HN(R₅)A—R₆ yielding intermediate g-7 after adeprotection reaction. Intermediate g-7 may then be reacted with anintermediate of formula R₁—L-(leaving group) in the present of a basesuch as triethylamine and optionally in the presence of EDC or analcohol such as t-butanol, and in a suitable solvent such asdichloromethane, thus obtaining the compound g-8 which is compound offormula (I).

[0145] Another particular way of preparing some compounds according tothe invention is depicted in scheme H.

[0146] After deprotection of the protective group of h-1 using methodsknown in the art, such as HCl in isopropanol when PG is a Boc group, thefree amine is reacted with a carboxylic acid , in the presence of acoupling agent such as EDC and HOBt, in an organic solvent such asdichloromethane, to yield h-2.

[0147] In one preferred embodiment, the carboxylic acid is theBoc-protected L-tert-Leucine.

[0148] h-2 is then deprotected as previously described and reacted withchloroacetic acid in the presence of EDC and HOBt, in dichloromethane,to give intermediate h-3, which is further substituted by a primaryamine in an organic solvent such as dimethyl formamide (DMF), underheating conditions, then protected by an adequate protective group suchas Boc, to give intermediate h-4.

[0149] Intermediate h-4 is reacted with meta-chloroperoxybenzoic acid indichloromethane to give the sulfoxide h-5, further substituted by anamine of formula NHR₃R₄ in an organic solvent such as acetonitrile,under heating conditions. The final compound h-6 is obtained afterremoval of the protective group as previously described.

[0150] The compounds of formula (I) may also be converted to thecorresponding N-oxide forms following art-known procedures forconverting a trivalent nitrogen into its N-oxide form as is shown forinstance for intermediate c-6 in scheme C. Said N-oxidation reaction maygenerally be carried out by reacting the starting material of formula(I) with an appropriate organic or inorganic peroxide. Appropriateinorganic peroxides comprise, for example, hydrogen peroxide, alkalimetal or earth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chloro-benzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert-butyl hydroperoxide. Suitable solvents are, for example, water,lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

[0151] An interesting group of intermediates are those intermediates offormula a-8, b-9 or d-1 wherein —A—R₆ is hydrogen. Said intermediatesmay also have pharmacological properties similar to thosepharmacological properties of the compounds of formula (I).

[0152] The present compounds can thus be used in animals, preferably inmammals, and in particular in humans as pharmaceuticals per se, inmixtures with one another or in the form of pharmaceutical preparations.

[0153] Furthermore, the present invention relates to pharmaceuticalpreparations which as active constituents contain an effective dose ofat least one of the compounds of formula (I) in addition to customarypharmaceutically innocuous excipients and auxiliaries. Thepharmaceutical preparations normally contain 0.1 to 90% by weight of acompound of formula (I). The pharmaceutical preparations can be preparedin a manner known per se to one of skill in the art. For this purpose,at least one of a compound of formula (I), together with one or moresolid or liquid pharmaceutical excipients and/or auxiliaries and, ifdesired, in combination with other pharmaceutical active compounds, arebrought into a suitable administration form or dosage form which canthen be used as a pharmaceutical in human medicine or veterinarymedicine.

[0154] Pharmaceuticals which contain a compound according to theinvention can be administered orally, parenterally, e.g., intravenously,rectally, by inhalation, or topically, the preferred administrationbeing dependent on the individual case, e.g., the particular course ofthe disorder to be treated. Oral administration is preferred.

[0155] The person skilled in the art is familiar on the basis of hisexpert knowledge with the auxiliaries which are suitable for the desiredpharmaceutical formulation. Beside solvents, gel-forming agents,suppository bases, tablet auxiliaries and other active compoundcarriers, antioxidants, dispersants, emulsifiers, antifoams, flavorcorrigents, preservatives, solubilizers, agents for achieving a depoteffect, buffer substances or colorants are also useful.

[0156] Due to their favorable pharmacological properties, particularlytheir activity against multi-drug resistant HIV protease enzymes, thecompounds of the present invention are useful in the treatment ofindividuals infected by HIV and for the prophylaxis of theseindividuals. In general, the compounds of the present invention may beuseful in the treatment of warm-blooded animals infected with viruseswhose existence is mediated by, or depends upon, the protease enzyme.Conditions which may be prevented or treated with the compounds of thepresent invention, especially conditions associated with HIV and otherpathogenic retroviruses, include AIDS, AIDS-related complex (ARC),progressive generalized lymphadenopathy (PGL), as well as chronic CNSdiseases caused by retroviruses, such as, for example HIV mediateddementia and multiple sclerosis.

[0157] The compounds of the present invention or any subgroup thereofmay therefore be used as medicines against above-mentioned conditions.Said use as a medicine or method of treatment comprises the systemicadministration to HIV-infected subjects of an amount effective to combatthe conditions associated with HIV and other pathogenic retroviruses,especially HIV-1. Consequently, the compounds of the present inventioncan be used in the manufacture of a medicament useful for treatingconditions associated with HIV and other pathogenic retroviruses, inparticular medicaments useful for treating patients infected withmulti-drug resistant HIV virus.

[0158] In a preferred embodiment, the invention relates to the use of acompound of formula (I) or any subgroup thereof in the manufacture of amedicament for treating or combating infection or disease associatedwith multi-drug resistant retrovirus infection in a mammal, inparticular HIV-1 infection. Thus, the invention also relates to a methodof treating a retroviral infection, or a disease associated withmulti-drug resistant retrovirus infection comprising administering to amammal in need thereof an effective amount of a compound of formula (I)or a subgroup thereof.

[0159] In another preferred embodiment, the present invention relates tothe use of formula (I) or any subgroup thereof in the manufacture of amedicament for inhibiting a protease of a multi-drug resistantretrovirus in a mammal infected with said retrovirus, in particularHIV-1 retrovirus.

[0160] In another preferred embodiment, the present invention relates tothe use of formula (I) or any subgroup thereof in the manufacture of amedicament for inhibiting multi-drug resistant retroviral replication,in particular HIV-1 replication.

[0161] The compounds of the present invention may also find use ininhibiting ex vivo samples containing HIV or expected to be exposed toHIV. Hence, the present compounds may be used to inhibit HIV present ina body fluid sample which contains or is suspected to contain or beexposed to HIV.

[0162] Also, the combination of an antiretroviral compound and acompound of the present invention can be used as a medicine. Thus, thepresent invention also relates to a product containing (a) a compound ofthe present invention, and (b) another antiretroviral compound, as acombined preparation for simultaneous, separate or sequential use intreatment of retroviral infections, in particular, in the treatment ofinfections with multi-drug resistant retroviruses. Thus, to combat ortreat HIV infections, or the infection and disease associated with HIVinfections, such as Acquired Immunodeficiency Syndrome (AIDS) or AIDSRelated Complex (ARC), the compounds of this invention may beco-administered in combination with for instance, binding inhibitors,such as, for example, dextran sulfate, suramine, polyanions, solubleCD4; fusion inhibitors, such as, for example, T20, T1249, SHC-C, PRO542;co-receptor binding inhibitors, such as, for example, AMD 3100(Bicyclams), TAK 779; RT inhibitors, such as, for example, foscarnet andprodrugs, MIV-310; nucleoside RTIs, such as, for example, AZT, 3TC, DDC,DDI, D4T, Abacavir, FTC, DAPD, dOTC; nucleotide RTIs, such as, forexample, PMEA, PMPA, tenofovir; NNRTIs, such as, for example,nevirapine, delavirdine, efavirenz, 8 and 9-Cl TIBO (tivirapine),loviride, TMC-125, TMC-120, MKC-442, UC 781, Capravirine, DPC 961,DPC₉₆₃, DPC082, DPC083, calanolide A, SJ-3366, TSAO, 4″-deaminated TSAO;RNAse H inhibitors, such as, for example, SP1093V, PD126338; TATinhibitors, such as, for example, RO-5-3335, K12, K37; integraseinhibitors, such as, for example, L 708906, L 731988; proteaseinhibitors, such as, for example, amprenavir, ritonavir, nelfinavir,saquinavir, indinavir, lopinavir, BMS 232632, BMS 186316, DPC 681, DPC684, tipranavir, AG1776, DMP 450, L 756425, PD178390, PNU 140135;glycosylation inhibitors, such as, for example, castanospermine,deoxynojirimycine.

[0163] The combination may provide a synergistic effect, whereby viralinfectivity and its associated symptoms may be prevented, substantiallyreduced, or eliminated completely.

[0164] The compounds of the present invention may also be administeredin combination with immunomodulators (e.g., bropirimine, anti-humanalpha interferon antibody, IL-2, methionine enkephalin, interferonalpha, and naltrexone) antibiotics (e.g., pentamidine isothiorate),vaccines or hormones (e.g growth hormone) to ameliorate, combat, oreliminate HIV infection and its symptoms.

[0165] For an oral administration form, compounds of the presentinvention are mixed with suitable additives, such as excipients,stabilizers or inert diluents, and brought by means of the customarymethods into the suitable administration forms, such as tablets, coatedtablets, hard capsules, aqueous, alcoholic, or oily solutions. Examplesof suitable inert carriers are gum arabic, magnesia, magnesiumcarbonate, potassium phosphate, lactose, glucose, or starch, inparticular, corn starch. In this case the preparation can be carried outboth as dry and as moist granules. Suitable oily excipients or solventsare vegetable or animal oils, such as sunflower oil or cod liver oil.Suitable solvents for aqueous or alcoholic solutions are water, ethanol,sugar solutions, or mixtures thereof. Polyethylene glycols andpolypropylene glycols are also useful as further auxiliaries for otheradministration forms.

[0166] For subcutaneous or intravenous administration, the activecompounds, if desired with the substances customary therefor such assolubilizers, emulsifiers or further auxiliaries, are brought intosolution, suspension, or emulsion. The compounds of formula (I) can alsobe lyophilized and the lyophilizates obtained used, for example, for theproduction of injection or infusion preparations. Suitable solvents are,for example, water, physiological saline solution or alcohols, e.g.ethanol, propanol, glycerol, in addition also sugar solutions such asglucose or mannitol solutions, or alternatively mixtures of the varioussolvents mentioned.

[0167] Suitable pharmaceutical formulations for administration in theform of aerosols or sprays are, for example, solutions, suspensions oremulsions of the compounds of formula (I) or their physiologicallytolerable salts in a pharmaceutically acceptable solvent, such asethanol or water, or a mixture of such solvents. If required, theformulation can also additionally contain other pharmaceuticalauxiliaries such as surfactants, emulsifiers and stabilizers as well asa propellant. Such a preparation customarily contains the activecompound in a concentration from approximately 0.1 to 50%, in particularfrom approximately 0.3 to 3% by weight.

[0168] In order to enhance the solubility and/or the stability of thecompounds of formula (I) in pharmaceutical compositions, it can beadvantageous to employ α-, β- or γ-cyclodextrins or their derivatives.Also co-solvents such as alcohols may improve the solubility and/or thestability of the compounds of formula (I) in pharmaceuticalcompositions. In the preparation of aqueous compositions, addition saltsof the subject compounds are obviously more suitable due to theirincreased water solubility.

[0169] Appropriate cyclodextrins are α-, β- or γ-cyclodextrins (CDs) orethers and mixed ethers thereof wherein one or more of the hydroxygroups of the anhydroglucose units of the cyclodextrin are substitutedwith C₁₋₆alkyl, particularly methyl, ethyl or isopropyl, e.g. randomlymethylated β-CD; hydroxyC₁₋₆alkyl, particularly hydroxyethyl,hydroxypropyl or hydroxybutyl; carboxyC₁₋₆alkyl, particularlycarboxymethyl or carboxyethyl; C₁₋₆alkylcarbonyl, particularly acetyl;C₁₋₆alkyloxycarbonylC₁₋₆alkyl or carboxyC₁₋₆alkyloxyC₁₋₆alkyl,particularly carboxymethoxypropyl or carboxyethoxypropyl;C₁₋₆alkylcarbonyloxyC₁₋₆alkyl, particularly 2-acetyloxypropyl.Especially noteworthy as complexants and/or solubilizers are β-CD,randomly methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD,2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD(2-HP-β-CD).

[0170] The term mixed ether denotes cyclodextrin derivatives wherein atleast two cyclodextrin hydroxy groups are etherified with differentgroups such as, for example, hydroxy-propyl and hydroxyethyl.

[0171] An interesting way of formulating the present compounds incombination with a cyclodextrin or a derivative thereof has beendescribed in EP-A-721,331. Although the formulations described thereinare with antifungal active ingredients, they are equally interesting forformulating the compounds of the present invention. The formulationsdescribed therein are particularly suitable for oral administration andcomprise an antifungal as active ingredient, a sufficient amount of acyclodextrin or a derivative thereof as a solubilizer, an aqueous acidicmedium as bulk liquid carrier and an alcoholic co-solvent that greatlysimplifies the preparation of the composition. Said formulations mayalso be rendered more palatable by adding pharmaceutically acceptablesweeteners and/or flavors.

[0172] Other convenient ways to enhance the solubility of the compoundsof the present invention in pharmaceutical compositions are described inWO-94/05263, PCT application No. PCT/EP98/01773, EP-A-499,299 and WO97/44014, all incorporated herein by reference.

[0173] More in particular, the present compounds may be formulated in apharmaceutical composition comprising a therapeutically effective amountof particles consisting of a solid dispersion comprising (a) a compoundof formula (I), and (b) one or more pharmaceutically acceptablewater-soluble polymers.

[0174] The term “a solid dispersion” defines a system in a solid state(as opposed to a liquid or gaseous state) comprising at least twocomponents, wherein one component is dispersed more or less evenlythroughout the other component or components. When said dispersion ofthe components is such that the system is chemically and physicallyuniform or homogenous throughout or consists of one phase as defined inthermo-dynamics, such a solid dispersion is referred to as “a solidsolution”. Solid solutions are preferred physical systems because thecomponents therein are usually readily bioavailable to the organisms towhich they are administered.

[0175] The term “a solid dispersion” also comprises dispersions whichare less homogenous throughout than solid solutions. Such dispersionsare not chemically and physically uniform throughout or comprise morethan one phase.

[0176] The water-soluble polymer in the particles is conveniently apolymer that has an apparent viscosity of 1 to 100 mPa.s when dissolvedin a 2% aqueous solution at 20° C. solution.

[0177] Preferred water-soluble polymers are hydroxypropylmethylcelluloses or HPMC. HPMC having a methoxy degree of substitutionfrom about 0.8 to about 2.5 and a hydroxypropyl molar substitution fromabout 0.05 to about 3.0 are generally water soluble. Methoxy degree ofsubstitution refers to the average number of methyl ether groups presentper anhydroglucose unit of the cellulose molecule. Hydroxy-propyl molarsubstitution refers to the average number of moles of propylene oxidewhich have reacted with each anhydroglucose unit of the cellulosemolecule.

[0178] The particles as defined hereinabove can be prepared by firstpreparing a solid dispersion of the components, and then optionallygrinding or milling that dispersion.

[0179] Various techniques exist for preparing solid dispersionsincluding melt-extrusion, spray-drying and solution-evaporation,melt-extrusion being preferred.

[0180] It may further be convenient to formulate the present compoundsin the form of nanoparticles which have a surface modifier adsorbed onthe surface thereof in an amount sufficient to maintain an effectiveaverage particle size of less than 1000 nm. Useful surface modifiers arebelieved to include those which physically adhere to the surface of theantiretroviral agent but do not chemically bond to the antiretroviralagent.

[0181] Suitable surface modifiers can preferably be selected from knownorganic and inorganic pharmaceutical excipients. Such excipients includevarious polymers, low molecular weight oligomers, natural products andsurfactants. Preferred surface modifiers include nonionic and anionicsurfactants.

[0182] Yet another interesting way of formulating the present compoundsinvolves a pharmaceutical composition whereby the present compounds areincorporated in hydrophilic polymers and applying this mixture as a coatfilm over many small beads, thus yielding a composition with goodbioavailability which can conveniently be manufactured and which issuitable for preparing pharmaceutical dosage forms for oraladministration.

[0183] Said beads comprise (a) a central, rounded or spherical core, (b)a coating film of a hydrophilic polymer and an antiretroviral agent and(c) a seal-coating polymer layer.

[0184] Materials suitable for use as cores in the beads are manifold,provided that said materials are pharmaceutically acceptable and haveappropriate dimensions and firmness. Examples of such materials arepolymers, inorganic substances, organic substances, and saccharides andderivatives thereof.

[0185] Another aspect of the present invention concerns a kit orcontainer comprising a compound of formula (I) in an amount effectivefor use as a standard or reagent in a test or assay for determining theability of a potential pharmaceutical to inhibit HIV protease, HIVgrowth, or both. This aspect of the invention may find its use inpharmaceutical research programs.

[0186] The compounds of the present invention can be used inhigh-throughput target-analyte assays such as those for measuring theefficacy of said compound in HIV treatment.

[0187] The compounds of the present invention can be used in phenotypicresistance monitoring assays, such as known recombinant assays, in theclinical management of resistance developing diseases such as HIV. Aparticularly useful resistance monitoring system is a recombinant assayknown as the Antivirogram™. The Antivirogram™ is a highly automated,high throughput, second generation, recombinant assay that can measuresusceptibility, especially viral susceptibility, to the compounds of thepresent invention. (Hertogs K, de Bethune M P, Miller V et al.Antimicrob Agents Chemother, 1998; 42(2):269-276, incorporated byreference).

[0188] The dose of the present compounds or of the physiologicallytolerable salt(s) thereof to be administered depends on the individualcase and, as customary, is to be adapted to the conditions of theindividual case for an optimum effect. Thus it depends, of course, onthe frequency of administration and on the potency and duration ofaction of the compounds employed in each case for therapy orprophylaxis, but also on the nature and severity of the infection andsymptoms, and on the sex, age, weight and individual responsiveness ofthe human or animal to be treated and on whether the therapy is acute orprophylactic. Customarily, the daily dose of a compound of formula (I)in the case of administration to a patient approximately 75 kg in weightis 1 mg to 1 g, preferably 3 mg to 0.5 g. The dose can be administeredin the form of an individual dose, or divided into several, e.g. two,three, or four, individual doses.

[0189] Experimental Part

Preparation of the Compounds of Formula (I) and their IntermediatesEXAMPLE 1 Preparation of Compound 29

[0190]

[0191] A mixture of 1.56 g of intermediate a-3 (R₂=H andR₄=—CH₂—CH₂—NH-(2-pyridinyl)) and 0.59 g of triethylamine in 50 ml ofdichloromethane was stirred at 0° C. Then 1.25 g of2-(acetylamino)-6-benzothiazolesulfonyl chloride, was added and thereaction mixture stirred overnight at room temperature. After washingwith water, the organic layer was separated, dried and the solventevaporated. The brown solid obtained was re-dissolved in methanol at 70°C., cooled and filtered off, yielding 1.9 g (75%) of intermediate a-4(R₂=H, R₄=—CH₂—CH₂—NH-(2-pyridinyl) and —A—R₆=H).

[0192] To a mixture of 6 g of intermediate a-4 (R₂=H,R₄=—CH₂—CH₂—NH-(2-pyridinyl) and —A—R₆=H) in 50 ml of dichloromethane,7.3 ml of trifluoracetic acid were added. The reaction mixture wasstirred at room temperature for 6 hours. Extra dichloromethane was addedand washed with NaHCO₃ solution. The organic layer was dried and thesolvent evaporated under reduced pressure, yielding 4.1 g (81%) ofintermediate a-5 (R₂=H, R₄=—CH₂—CH₂—NH-(2-pyridinyl) and —A—R₆=H).

[0193] A mixture of 0.60 g of intermediate a-5 (R₂=H,R₄=—CH₂—CH₂—NH-(2-pyridinyl) and —A—R₆=H), 0.29 g of1-[[[[(3S,3aR,6aS)+(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl]oxy]-2,5-pyrrolidinedione(prepared analogously to the procedure described in WO9967417) and 0.33g of triethylamine in 15 ml of dichloromethane was stirred at roomtemperature for 24 hours. Solvents were evaporated and the solidobtained was redissolved in methanol at 70° C., cooled and filtered off,yielding 0.53 g (69%) of compound 29. Mass Spectral data: m/z=711 (M+H)

EXAMPLE 2 Preparation of Compound 31

[0194]

[0195] A mixture of 540 mg of intermediate a-5 (R₂=H,R₄=—CH₂-(2-pyridinyl) and —A—R₆=H), 135 mg of tert-butanol, 192 mg ofEDC and 101 mg of triethylamine in 5 ml of dichloromethane, was stirredovernight at room temperature. The reaction mixture was then washed witha Na₂CO₃ solution and brine. The organic layer was separated, dried andthe solvent evaporated. The residue was purified by preparative-HPLC,yielding 184 mg (26%) of compound 31. Mass spectral data m/z=702 (M+H)

EXAMPLE 3 Preparation of Compound 33

[0196]

[0197] A mixture of 540 mg of intermediate a-5 (R₂=H,R₄=—CH₂-(2-pyridinyl) and —A—R₆=H), 271 mg of1-[[[[(3S,3aR,6aS)+(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl]oxy]-2,5-pyrrolidinedioneand 101 mg of triethylamine in 5 ml of dichloromethane was stirred atroom temperature for 24 hours. The reaction mixture was then washed witha Na₂CO₃ solution and brine. The organic layer was separated, dried andthe solvent evaporated. The residue was purified by preparative-HPLC,yielding 161 mg (23%) of compound 33. Mass spectral data: m/z=696 (M+H)

EXAMPLE 4 Preparation of Compound 2

[0198]

[0199] To a mixture of 0.3 g of racemic intermediate a-8 (R₂=H,R₄=isobutyl, —A—R₆=H and—L—R₁=[[hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl) and 0.061 gtriethylamine in anhydrous dioxane is added in several portions 0.18 gethyl chloroformate. The reaction mixture was heated overnight to 60° C.To the mixture is added 10 ml water and 0.4 g potassium carbonatefollowed by 2 hours of stirring. Dioxane was removed in vacuo. Theaqueous phase was extracted with dichloromethane. The combined organicphase was concentrated and the obtained residue purified bychromatography yielded 0.23 g (68%) of compound 2.

EXAMPLE 5 Preparation of Compound 56

[0200]

[0201] A mixture of 19.66 g of[2R-hydroxy-3-[(2-methylpropyl)amino]-1S-(phenylmethyl)-propyl]-carbamicacid, 1,1-dimethylethyl ester (described in WO97/18205) and 17.76 g oftriethylamine in 200 ml of dichloromethane is stirred at 0° C. for 20minutes under inert atmosphere. 18.72 g of2-(acetylamino)-6-benzothiazolesulfonyl chloride was added in smallportions and the mixture was then stirred at room temperature for 2hours. After washing with 5% HCl solution, saturated sodium bicarbonatesolution and brine, the organic layer was dried and the solventevaporated under reduced pressure. The crude product was purified onsilica gel eluting with 4% methanol in dichloromethane yielding 30.82 g(90%) of intermediate b-4 (R₂=H and R₄=isobutyl).

[0202] To a mixture of 13.75 g of intermediate b-4 (R₂=H andR₄=isobutyl) in 130 ml of ethanol/dioxane (1:1) 65 ml of HCl (5 to 6 Nin isopropanol) was added. The reaction was stirred at 50° C. for 22hours. After evaporating, the salt was treated with saturated sodiumbicarbonate solution and extracted with dichloromethane. The organiclayer was dried, the solvent evaporated and the residue purified onsilica gel eluting with 3% methanol in dichloromethane yielding 18.36 g(72%) of intermediate b-5 (R₂=H and R₄=isobutyl).

[0203] A solution of 1.81 g of sodium nitrite in 10 ml of water wasadded over a 40-min period to a mixture of 9.80 g of intermediate b-5(R₂=H and R₄=isobutyl) in 180 ml of 85% phosphoric acid held at −10° C.After being stirred for 1.5 hour, the mixture was added to a stirredsolution of 10.90 g of copper sulphate pentahydrate and 12.67 g ofsodium chloride in 80 ml of water at −10° C. The mixture was stirred for1.5 hour , being allowed to warm to room temperature, and then madealkaline (pH=8) with an ammonium hydroxide solution under cooling. Theresulting solution was extracted with ethylacetate. After drying andevaporating the solvent, 7.59 g (74%) of intermediate b-6 (R₂=H andR₄=isobutyl) was obtained.

[0204] A mixture of 1.63 g of intermediate b-6 (R₂=H and F4=isobutyl),0.80 g of1-[[[[(3S)-tetrahydro-3-furanyl]oxy]carbonyl]oxy]-2,5-pyrrolidinedioneand 0.53 g of triethylamine in 50 ml of dichloromethane was stirred atroom temperature for 5 hours. After evaporation of dichloromethane underreduced pressure, the crude product was purified on silica gel elutingwith 3% of methanol in dichloromethane yielding 0.58 g (29%) ofintermediate b-8 (R₂=H, R₄=isobutyl,R₁—L—=[[(3S)-tetrahydro-3-furanyl]oxy]carbonyl).

[0205] To a solution of 0.23 g of intermediate b-8 (R₂=H, R₄=isobutyl,R₁—L—=[[(3S)-tetrahydro-3-furanyl]oxy]carbonyl) in 30 ml of acetonitrilewas added 0.20 g of N,N-dimethylethylenediamine. This solution wasstirred at 80° C. for 4 hours. After evaporation of acetonitrile underreduced pressure, the crude product was purified on silica gel elutingwith 2% of methanol in dichloromethane yielding 0.12 g (50%) of compound56. Mass spectral data: m/z=634 (M+H)

EXAMPLE 6 Preparation of Compound 44

[0206]

[0207] To a solution of 0.90 g of intermediate b-6 (R₂=H andR₄=isobutyl) in 20 ml of acetonitrile was added 0.85 g ofN,N-dimethylethylenediamine. This solution was stirred at 80° C. for 3hours. After evaporation of acetonitrile under reduced pressure, theproduct was washed with 2% sodium carbonate and extracted withethylacetate. The organic layer was dried, the solvent evaporated underreduced pressure and purified on silica gel eluting with 1% of ammoniain dichloromethane, yielding 0.57 g (58%) of intermediate b-7 (R₂=H,R₄=isobutyl and —A—R₆=CH₂CH₂N(CH₃)₂).

[0208] A mixture of 0.65 g of(±trans)-4-(dimethylamino)tetrahydro-3-furanol (synthesis described inU.S. Pat. No. 3,265,711), 3.78 g of disuccinimidyl carbonate and 1.50 gof triethylamine in 30 ml of dichloromethane was stirred at roomtemperature for 24 hours. After washing the resulting solution withsaturated sodium bicarbonate, the organic layer was dried and thesolvent evaporated under reduced pressure to give 0.52 g (38%) of(±trans)-1-[[[[4-(dimethylamino)-tetrahydro-furan-3-yl]oxy]-carbonyl]oxy]-2,5-pyrrolidinedione.

[0209] A mixture of 0.25 g of intermediate b-7 (R₁=H, R₂=CH₂CH₂N(Me)₂),0.13 g(±trans)-1-[[[[4-(dimethylamino)-tetrahydro-furan-3-yl]oxy]carbonyl]oxy]-2,5-pyrrolidinedioneand 0.07 g of triethylamine in 15 ml of dichloromethane was stirred atroom temperature for 24 hours. After evaporation of dichloromethaneunder reduced pressure, the crude product was purified on silica geleluting with 4% of ammonia in dichloromethane, yielding 0.14 g (43%) ofcompound 44. Mass spectral data: m/z=677 (M+H)

EXAMPLE 7 Preparation of Compound 19

[0210]

[0211] To a solution of 0.83 g of intermediate b-6 (R₂=H andR₄=isobutyl) in 20 ml of acetonitrile was added 0.40 g ofN-(2-aminoethyl)-pyrrolidine. This solution was stirred at 80° C. for 4hours. After evaporation of acetonitrile under reduced pressure, theproduct was washed with 2% sodium carbonate and extracted withethylacetate. The organic layer was dried, evaporated under reducedpressure and purified on silica gel eluting with 1% of ammonia indichloromethane, yielding 0.47 g (49%) of intermediate b-7 (R₂=H,R₄=isobutyl and —A—R₆ =CH₂CH₂-(1-pyrrolidinyl)).

[0212] A mixture of 0.47 g of intermediate b-7 (R₂=H, R₄=isobutyl and—A—R₆=CH₂CH₂-(1-pyrrolidinyl)) 0.24 g of1-[[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]-carbonyl]oxy]-2,5-pyrrolidinedioneand 0.10 g of triethylamine in 20 ml of dichloromethane was stirred atroom temperature for 24 hours. After evaporation of dichloromethaneunder reduced pressure, the crude product was purified on silica geleluting with 2% of ammonia in dichloromethane, yielding 0.54 g (88%) ofintermediate b-9 (R₂=H, R₄=isobutyl, —A—R₆=CH₂CH₂-(1-pyrrolidinyl) and—L—R₁=[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl).

[0213] To a solution of 0.54 g of intermediate b-9 (R₂=H, R₄=isobutyl,—A—R₆=CH₂CH₂-(1-pyrrolidinyl) and—L—R₁=[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]-carbonyl) and0.16 g of triethylamine in 40 ml of dichloromethane under inertatmosphere was added 0.22 g of acetyl chloride. After stirring at roomtemperature for 2 hours and washing with water, the organic layer wasdried and evaporated under reduced pressure to give 0.50 g (87%) ofcompound 19. Mass spectral data: m/z=744 (M+H)

EXAMPLE 8 Preparation of Compound 16

[0214]

[0215] To a solution of 4.91 g of[(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)-amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamicacid, 1,1-dimethylethyl ester (prepared as described in U.S. Pat. No.6,140,505) in 40 ml of anhydrous tetrahydrofuran, was added 1.78 g of1,1′-thiocarbonyldiimidazole. This solution was refluxed 4 hours. Aftercooled at 25° C. 0.88 g of N,N-dimethylethylamine was added and thenthis solution was again refluxed 16 hours. After cooling at 25° C.,evaporation of tetrahydrofuran under reduced pressure, dichloromethanewas added, washed with water, the organic phase was dried andconcentrated. This crude product was purified on silica gel eluting with5% of methanol in dichloromethane, yielding 3.8 g (62%) of intermediatec-2 (R₂=H, R₄=isobutyl). Mass spectral data: m/z=622 (M+H), 566, 532.

[0216] To a solution of 2.5 g of the intermediate c-2 (R₂=H,R₄=isobutyl) in 10 ml of acetic acid was added a solution of 0.64 g ofbromine in 10 ml acetic acid. After 2 hours, this crude product wasconcentrated, dichloromethane added and this organic phase washed with asaturated potassium carbonate solution. The organic phase was dried onmagnesium sulfate, filtered and concentrated, yielding intermediate c-3(R₂=H, R₄=isobutyl). Mass spectral data: m/z=620 (M+H), 564, 520, 261.

[0217] The intermediate c-3 (R₂=H, R₄=isobutyl) was diluted with 20 mlof dichloromethane and 5 ml of trifuoroacetic acid were added. Thissolution was stirred for 1 hour and then concentrated. This residue waswashed with a potassium carbonate solution and extracted withdichloromethane. This crude material was purified on silica gel elutingwith 5% of methanol in dichloromethane yielding 1.5 g (72%) of theintermediate c-4 (R₂=H, R₄=isobutyl).

[0218] 1.5 g of the intermediate c4 (R₂=H, R₄=isobutyl), 0.81 g of1-[[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl]oxy]-2,5-pyrrolidinedione0.67 g of triethylamine in 5 ml of dichloromethane was stirred for 4hours at room temperature. This crude product was directly purified onsilica gel eluting with 5% methanol in dichloromethane, yielding 0.80 g(39%) of compound 16.

EXAMPLE 9 Preparation of Compound 27

[0219]

[0220] To 0.34 g of compound 16 in 5 ml of dichloromethane was added0.08 g of sodium bicarbonate and 0.15 g (75%) of meta chloroperbenzoicacid. This solution was stirred 2 hours at room temperature. Water wasadded and the residue was extracted with dichloromethane. The organicphase was dried on magnesium sulfate, filtered and concentrated. Thiscrude material was purified on silica gel eluting with 5% of methanol indichloromethane yielding 0.09 g (26%) of compound 27. Mass spectraldata: m/z=692 (M+H)

EXAMPLE 10 Preparation of Compound 11

[0221]

[0222] To a mixture of 2.32 g2-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)-6-benzothiazolesulfonamideand 1.0 g triethylamine in dichioromethane was added 1.47 g1-[[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl]-oxy]-2,5-pyrrolidinedione.After overnight stirring the reaction mixture was washed with asaturated sodium bicarbonate solution, dried over magnesium sulfate,filtered and concentrated. The obtained residue was purified by column(dichloromethane:methanol 95:5) to afford 2.76 g intermediate d-1 (R₂=H,R₄=isobutyl, —A—R₆=H and—L—R₁=[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl) (88%).

[0223] To a mixture of intermediate d-1 (R₂=H, R₄=isobutyl, —A—R₆=H and—L—R₁=[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl) (2.0g; 3.3 mmole) and triethylamine (1.16 g; 11.5 mmole) in dry 1,4-dioxaneis added chloroacetylchloride (429 mg; 3.8 mmole). The resulting mixturewas stirred at rt for 3 hours. Another portion of chloroacetylchloride(180 mg; 1.5 mmole) was added and stirring was continued for 3 hours.After evaporation of the solvent the residue was purified bychromatography (dichloromethane:methanol 98:2) to afford 1.57 g (70%) ofintermediate d-2 (R₂=H, R₄=isobutyl, —A—R₆=H and—L—R₁=[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl). Massspectral data: (ES+): 681/683(M+H).

[0224] To a solution of the intermediate d-2 (R₂=H, R₄=isobutyl, —A—R₆=Hand —L—R₁=[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl)(0.45 g; 0.66 mmole) in tetrahydrofuran was added 4.6 ml of an 40% wtaqueous dimethylamine solution. After stirring for two hourstetrahydrofuran was evaporated. The aqueous layer was extracted withdichloromethane. The combined organic layers were dried over magnesiumsulfate. Concentration in vacuo yielded 0.42 g (92%) of compound 11.

[0225] Mass spectral data: (ES+): 690 (M+H), 560.

EXAMPLE 11 Preparation of Compound 12

[0226]

[0227] To a solution of the intermediate d-2 (R₂=H, R₄=isobutyl, —A—R₆=Hand —L—R₁=[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl) indichloromethane was 1.5 eq. of pyrrolidine together with sodiumcarbonate as a base. After overnight stirring at room temperature thesolvent was removed in vacuo. The residue was purified by chromatography(dichloromethane:methanol) to yield 76% of compound 12. Mass spectraldata: (ES+) 715 (M+H)

EXAMPLE 12 Preparation of Compound 43

[0228]

[0229] A mixture of 6.13 g of intermediate e-1 (R₂=H, R₄=isobutyl and—A—R₆=H) and 10 g sodium carbonate in water/dioxane (1/2) was heated to80° C. for 48 hours. Dioxane was removed in vacuo. The resulting aqueousphase was extracted twice with ethyl acetate. After drying overmagnesium sulfate and filtration the combined organic phase wasconcentrated to yield 5.08 g of intermediate e-2 (R₂=H, R₄=isobutyl and—A—R₆=H). Mass spectral data (ES+): 549(M+H), 449.

[0230] To a mixture of 3.0 g 2-aminobenzothiazole intermediate e-2(R₂=H, R₄=isobutyl and —A—R₆=H) and 1.1 g triethylamine in dry1,4-dioxane was added 0.77 g chloroacetylchloride. The resulting mixturewas stirred overnight. After evaporation of the solvent the residue waspurified by chromatography (dichloromethane:methanol 98:2) to afford 2.7g (78%) of intermediate e-3 (R₂=H, R₄=isobutyl and —A—R₆=H). Massspectral data (ES+): 625/627(M+H).

[0231] To a solution of 0.8 g intermediate e-3 (R₂=H, R₄=isobutyl and—A—R₆=H) in tetrahydrofuran was added 8 ml of an 40% wt aqueousdimethylamine solution. After stirring for three hours tetrahydrofuranwas evaporated. The aqueous layer was extracted with dichloromethane.The combined organic layers were dried over magnesium sulfate.Concentration in vacuo provided 0.58 g (85%) of intermediate e-4 (R₂=H,R₄=isobutyl, —A—R₆=H and R_(a)═R_(b)=CH₃). Mass spectral data (ES+):634(M+H), 534.

[0232] To a solution of intermediate e-4 (R₂=H, R₄=isobutyl, —A—R₆=H andR_(a)═R_(b)=CH₃) in dichloromethane was added trifluoracetic acid (10equivalents). After overnight stirring the organic phase was washed withsaturated sodium bicarbonate and brine, dried over magnesium sulfate,filtered and concentrated to afford the intermediate e-5 (R₂=H,R₄=isobutyl, —A—R₆=H and R_(a)═R_(b)=CH₃).

[0233] To a solution of 0.35 g 4-amino-2-methylbenzoic acid indichloromethane was added at 0° C. 0.09 g 1-hydroxybenzotriazole and0.13 g EDC. After one half hour of stirring the temperature was allowedto rise to room temperature and stirring was continued for one morehour. After addition of the intermediate e-5 (R₂=H, R₄=isobutyl, —A—R₆=Hand R_(a)═R_(b)=CH₃) the reaction mixture was stirred at roomtemperature for two days. Then the solvent was removed in vacuo and theobtained residue was purified by chromatography(dichloromethane:methanol 97:3) to afford 0.12 g (29%) of compound 43.Mass spectral data (ES+): 667(M+H).

EXAMPLE 13 Preparation of the Intermediate f-2 (R₂=H andR₄=—CH₂-(2-pyridinyl))

[0234]

[0235] 25 g of 2-pyridylmethylamine was stirred at reflux in 400 ml ofisopropanol. Then a solution of 21 g of the2S,3S-1,2-epoxy-3-(tert-butoxycarbonylamino)-4-phenylbutane,commercially available, in 200 ml of isopropanol was added dropwise. Thereaction mixture was stirred overnight at reflux. After evaporation ofthe solvent, the residue was redissolved in dichloromethane and washed 4times with water. The organic layer was dried and evaporated. Theresidue obtained was purified by chromatography (dichloromethane:7N NH₃in methanol, 98:2) to afford 24 g (84%) of intermediate f-2 (R₂=H andR₄=—CH₂-(2-pyridinyl)).

EXAMPLE 14 Preparation of Compound 20

[0236] Compound 20 may also be prepared according to the method depictedin scheme G. The specific method is illustrated hereunder in scheme I.

[0237] Chlorosulfonic acid (0.193 kg; 1.65 mol) was stirred at 10° C.under nitrogen. i-1 was added carefully. The reaction mixture wasstirred for 3 hours at 90° C. The heating was stopped andthionyichioride (0.079 kg; 0.66 mol) was added slowly. The reactionmixture was stirred for another hour at 90° C. The reaction mixture wascooled until 35° C. and then 200 ml ethylacetate was added slowly.Another 200 ml of ethylacetate was added quickly after the beginning ofthe product precipitation. The precipitate was filtered and washed twicewith 200 ml ethylacetate and twice with 1000 ml cold water. Theprecipitate was then stirred in a NaHCO₃ solution until pH=7. Thismixture was filtered and the white solid i-2 was dried in a vacuum ovenat 50° C. (0.123 kg, 80%). (LC/MS MW⁺; 280,282)

[0238] A mixture of 0.120 kg (0.36 mol) of intermediate i-3 and 0.073 kg(0.72 mol) of triethylamine in 2-methyltetrahydrofuran (1.150 kg) wasstirred at 35° C. until dissolution of the reactants. Then 0.100 kg(0.36 mol) of intermediate i-2 was added and the reaction mixture wasstirred for 1.5 hours at 55° C. After washing the reaction mixture withwater (0.500 kg), the organic layer was separated and washed with 0.500kg 1.5 N HCl solution. Then the organic layer was separated, dried andevaporated yielding i-4; 0.208 kg (100%). (LC/MS MW⁺; 480,481,482)

[0239] 0.208 kg (0.36 mol) of intermediate i-4 was stirred in a mixtureof 1 kg 2-methyltetrahydrofuran, 0.060 kg H₂O and 0.110 kg ethanol at40° C. until dissolution of all the reactants. Then magnesiummonoperoxyphtalate hexahydrate 0.200 kg (0.4 mol) was added. The mixturewas stirred and heated for 15 min at 60° C. The reaction mixture wasmade alkaline with 0.400 kg Na₂CO₃ until pH=10. Intermediates i-5 andi-6. (about 70% i-5 and 30% i-6). (LC/MS MW⁺i-5; 496,497,498 MW⁺i-6;511,513) To this reaction mixture was added at 60° C. 0.050 kg (0.43mol) N-(2-aminoethylpyrrolidine. This mixture was stirred for 20 hoursat 70° C. Then the slurry was cooled to 40° C. and HCl concentrated (12N) was added dropwise until pH=7-8. A phase precipitation was thenobserved. The organic layer was separated, evaporated and dried in thevacuum oven at 50° C. yielding Boc N-protected i-7; 0.217 kg (93%).(LC/MS MW⁺; 646,647,648)

[0240] 0.217 kg (0.36 mol) of intermediate Boc N-protected i-7 wasdissolved in 1.4 kg isopropanol at 50° C. Then 0.370 L HCl 5 à 6 N (2mol) was added and the mixture was heated and stirred for 2.5 hours at70° C. This hot reaction mixture was added dropwise to 0.50 kg cold (0°C.-15° C.) isopropanol. The precipitate was filtered and washed withdiisopropyl ether. The slightly brown solid was triturated in aDIPE/toluene (50/50) mixture and then filtered and dried in the vacuumoven at 50° C., yielding 0.170 kg (76%) of i-7 HCl-salt. (LC/MS MW⁺;546,547,548).

[0241] A mixture of 1.3 g of intermediate i-7 ,0.774 g of1-[[[[(3S,3aR,6aS)+(3R,3aS,6R)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl]oxy]-2,5-pyrrolidinedione(prepared analogously to the procedure described in WO9967417) and 0.33g of triethylamine in 100 ml of dichloromethane was stirred at roomtemperature for 24 hours. This crude product was wahed with NaHCO3solution. The organic layer was dried and the solvant evaporated underreduced pressure. The residue was purified on silica gel, yielding 0.74g (45%) of compound 20. Mass spectra data: m/z=702(M+H).

EXAMPLE 15 Preparation of the Compound 85 and itsIntermediatesR₁=isobutyl)

[0242]

[0243] This compound was prepared following the procedure depicted inscheme H.

[0244] 11 g of intermediate h-1 (PG=Boc, R₁=isobutyl)[(1S,2R)-2-hydroxy-3-[(2-methylpropyl)[[2-(methylthio)-benzothiazol-6-yl]sulfonyl]amino]-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester were dissolved in300 mL of HCl in isopropanol and 100 mL of dichloromethane and thesolution was stirred at room temperature overnight. The reaction mixturewas then concentrated and treated with a mixture of dichloromethane andsodium hydroxide in water. The organic layer was then dried over MgSO₄and evaporated to give 8.8 g (97%) of the deprotected intermediateN-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)[2-(methylthio)-benzothiazol-6-yl]sulfonamide,as a free base. Mass spectral data: m/z=480 (M+H).

[0245] 4.15 g of the previous intermediate, 2 g of Boc-L-tert-Leucine,1.17 g of HOBt and 1.66 g of EDC were dissolved in 150 mL ofdichloromethane and stirred at room temperature overnight. The reactionmixture was then successively washed with a solution of NaHCO3 in water,brine, dried over MgSO₄ and evaporated to give 6 g (100%) ofintermediate h-2[(1S)-1-[[[(1S,2R)-2-hydroxy-3-[(2-methylpropyl)[(2-(methylthio)-benzothiazol-6-yl)sulfonyl]amino]-1-(phenylmethyl)propyl]amino]-carbonyl]-2,2-dimethylpropylacid,1,1-dimethylethyl ester. Mass spectral data: m/z=693 (M+H).

[0246] 6 g of intermediate h-2 were dissolved in 100 mL of HCl inisopropanol, and stirred at room temperature during 2 h. The reactionmixture was then concentrated and treated with a mixture ofdichloromethane and a solution of sodium carbonate in water. The organicphase was then washed with brine, dried over MgSO₄ and evaporated togive 3.9 g (76%) of the deprotected intermediate as a free base. Massspectral data: m/z=593 (M+H).

[0247] 3.9 g of the previous intermediate, 0.69 g of chloroacetic acid,0.98 g of HOBt, and 1.38 g of EDC were dissolved in 100 mL ofdichloromethane and stirred at RT overnight. The reaction mixture wasthen washed with brine, dried over MgSO₄ and evaporated. The crudecompound was purified on silica gel eluting with 0 to 5% methanol indichloromethane, yielding 3.72 g (85%) of the desired intermediate h-32-[(chloroacetyl)amino]-3,3-dimethyl-N-[(1S,2R)-2-hydroxy-3-[(2-methylpropyl)[[2-(methylthio)-benzothiazol-6-yl]sulfonyl]amino]-1-(phenylmethyl)propyl]-(2S)-butanamide.Mass spectral data: m/z=669 (M+H).

[0248] 3.72 g of intermediate h-3 and 1.27 mL of meta-fluorobenzylaminewere dissolved in DMF and stirred at 60° C. during 2 h. The reactionmixture was then concentrated and treated with a mixture ofdichloromethane and a solution of sodium carbonate in water.

[0249] The organic phase was then dried over MgSO₄ and evaporated toyield 4.3 g (100%) of the desired intermediateN′-[(3-fluorophenyl)methyl]glycyl-N-[(1S,2R)-2-hydroxy-3-[(2-methylpropyl)[[2-(methylthio)benzothiazol-6-yl]sulfonyl]amino]-1-(phenylmethyl)propyl]-3-methyl-L-Valinamide.Mass spectral data: m/z=758 (M+H).

[0250] 4.2 g of the previous intermediate, 1.2 g of Boc₂O and 0.77 mL oftriethylamine were dissolved in 50 mL of dichloromethane. The reactionmixture was stirred overnight at room temperature and 1.2 g of Boc₂Owere added. After 5 h, the reaction mixture was successively washed witha solution of sodium carbonate in water, brine, dried over MgSO₄ andevaporated. The crude compound was purified on silica gel eluting with 2to 5% methanol in dichloromethane, yielding 3.2 g (67%) of the desiredintermediate h-4N′-[(1,1-dimethylethoxy)carbonyl]-N′-[(3-fluorophenyl)methyl]glycyl-N-[(1S,2R)-2-hydroxy-3-[(2-methylpropyl)[[2-(methylthio)benzothiazol-6-yl]sulfonyl]amino]-1-(phenylmethyl)propyl]-3-methyl-L-Valinamide.Mass spectral data: m/z=858 (M+H).

[0251] 3.2 g of intermediate h-4 and 0.92 g of meta-chloroperoxybenzoicacid (mCPBA) were reacted in 100 mL of dichloromethane, at roomtemperature, during 1 h30. The reaction mixture was then washed with asolution of sodium carbonate in water, dried over MgSO₄ and evaporatedto yield 3.45 g (100%) of the desired intermediate h-5N′-[(1,1-dimethylethoxy)carbonyl]-N′-[(3-fluorophenyl)methyl]glycyl-N-[(1S,2R)-2-hydroxy-3-[(2-methylpropyl)[[2-(methylsulfinyl)benzothiazol-6-yl]sulfonyl]amino]-1-(phenylmethyl)propyl]-3-methyl-L-Valinamide.Mass spectral data: m/z=874 (M+H).

[0252] 0.5 g of intermediate h-5 was reacted with 0.16 mL ofN-(2-aminoethyl)pyrrolidine in 10 mL of acetonitrile, at 60° C., during1 h30. The reaction mixture was then evaporated and purified on silicagel eluting with 5 to 10% methanol in dichloromethane, yielding 0.24 g(46%) of the desired intermediateN′-[(1,1-dimethylethoxy)carbonyl]—N′-[(3-fluorophenyl)methyl]glycyl-N-[(1S,2R)-2-hydroxy-3-[(2-methylpropyl)[[2-[2-(pyrrolidin-1-yl)ethylamino]benzothiazol-6-yl]sulfonyl]amino]-1-(phenylmethyl)propyl]-3-methyl-L-Valinamide.Mass spectral data: m/z=924 (M+H).

[0253] 0.15 g of the previous intermediate was dissolved in 5 mL of HClin isopropanol. The reaction mixture was stirred at room temperatureduring 2 h, then evaporated. The crude compound was purified bypreparative HPLC, yielding 60 mg of the desired final compound 85N′-[(3-fluorophenyl)methyl]glycyl-N-[(1S,2R)-2-hydroxy-3-[(2-methylpropyl)[[2-[2-(pyrrolidin-1-yl)ethylamino]benzothiazol-6-yl]sulfonyl]amino]-1-(phenylmethyl)propyl]-3-methyl-L-Valinamide,bis-trifluoroacetate, obtained as a TFA salt. Mass spectral data:m/z=824 (M+H).

EXAMPLE 16 Preparation of the Compound 86R₁=isobutyl)

[0254]

[0255] 0.5 g of intermediate h-5 was reacted with 0.16 mL of3-(dimethylamino)propylamine in 10 mL of acetonitrile, at 60° C., during2 h. The reaction mixture was then evaporated, yielding 0.54 g (100%) ofthe desired intermediateN′-[(1,1-dimethylethoxy)carbonyl]-N′-[(3-fluorophenyl)methyl]glycyl-N-[(1S,2R)-2-hydroxy-3-[[[2-[3-(dimethylamino)propylamino]benzothiazol-6-yl]sulfonyl](2-methylpropyl)amino]-1-(phenylmethyl)propyl]-3-methyl-L-Valinamide.Mass spectral data: m/z=912 (M+H).

[0256] 0.54 g of the previous intermediate was dissolved in 10 mL of HClin isopropanol. The reaction mixture was stirred at room temperatureduring 2 h, then evaporated. The crude compound was purified bypreparative HPLC, yielding 83 mg of the desired final compound 86N′-[(3-fluorophenyl)methyl]glycyl-N-[(1S,2R)-2-hydroxy-3-[[[2-[3-(dimethylamino)propylamino]benzothiazol-6-yl]sulfonyl](2-methylpropyl)amino]-1-(phenylmethyl)propyl]-3-methyl-L-Valinamide,bis-trifluoroacetate, obtained as a TFA salt. Mass spectral data:m/z=812 (M+H).

EXAMPLE 17 Preparation of the Compounds 87 (R₁=isobutyl)

[0257]

[0258] 0.5 g of intermediate h-5 was reacted with 0.18 mg of N-methyl,N-(2-morpholin-4-ylethyl)amine in 10 mL of acetonitrile, at 60° C.,overnight. 0.9 g of N-methyl, N-(2-morpholin-4-ylethyl)amine was thenadded again to the reaction mixture, which was further stirred duringtwo days. The reaction mixture was then evaporated and purified onsilica gel eluting with 5% methanol in dichloromethane, yielding 0.6 g(100%) of the desired intermediateN′-[(1,1-dimethylethoxy)carbonyl]-N′-[(3-fluorophenyl)methyl]glycyl-N-[(1S,2R)-2-hydroxy-3-[[[2-[N-methyl,N-(2-morpholin-4-ylethyl)amino]benzothiazol-6-yl]sulfonyl](2-methylpropyl)amino]-1-(pheriylmethyl)propyl]-3-methyl-L-Valinamide.Mass spectral data: m/z=954 (M+H).

[0259] 0.6 g of the previous intermediate was dissolved in 100 mL of HClin isopropanol. The reaction mixture was stirred at room temperatureduring 2 h, then evaporated and treated with a mixture ofdichioromethane and a solution of sodium carbonate in water. The organicphase was then dried over MgSO₄ and evaporated. The crude compound waspurified by preparative HPLC, yielding 424 mg (60%) of the desired finalcompound 87N′-[(3-fluorophenyl)methyl]glycyl-N-[(1S,2R)-2-hydroxy-3-[[[2-[N-methyl,N-(2-morpholin-4-ylethyl)amino]benzothiazol-6-yl]sulfonyl](2-methylpropyl)amino]-1-(phenylmethyl)propyl]-3-methyl-L-Valinamide,bis-trifluoroacetate, obtained as a TFA salt. Mass spectral data:m/z=854 (M+H).

[0260] The following tables list the compounds of formula (I) which wereprepared following one of the above reaction schemes. TABLE 1

Co. No. Scheme R_(a) salt form/stereochemistry of bicyclic ring 1 A—NH—CO—CH₃ free base/(3R,3aS,6aR) + (3S,3aR,6aS) 2 A —NH—COO—C₂H₅ freebase/(3R,3aS,6aR) + (3S,3aR,6aS) 3 D —NH—CO—CH₂—N(CH₃)₂ freebase/(3R,3aS,6aR) + (3S,3aR,6aS) 4 B —NH—(CH₂)₂—N(CH₃)₂ freebase/(3R,3aS,6aR) + (3S,3aR,6aS) 5 D

free base/(3R,3aS,6aR) + (3S,3aR,6aS) 6 D —NH—CH₂—COOCH₃ freebase/(3R,3aS,6aR) + (3S,3aR,6aS) 7 D

free base/(3R,3aS,6aR) + (3S,3aR,6aS) 8 D

HCl (1:1)/(3R,3aS,6aR) + (3S,3aR,6aS) 9 A —N(CH₃)—COCH₃ freebase/(3R,3aS,6aR) + (3S,3aR,6aS) 10 D

free base/(3R,3aS,6aR) + (3S,3aR,6aS) 11 D —NH—CO—CH₂—N(CH₃)₂ freebase/(3R,3aS,6aR) 12 D

free base/(3R,3aS,6aR) 13 D

fumarate (1:1)/(3R,3aS,6aR) 14 D

HCl (1:1)/(3R,3aS,6aR) 15 D

oxalate (1:1)/(3R,3aS,6aR) 16 C —NH—(CH₂)₂—(CH₃)₂ free base/(3R,3aS,6aR)17 D

free base/(3R,3aS,6aR) 18 B

free base/(3R,3aS,6aR) 19 B

free base/(3R,3aS,6aR) 20 B

free base/(3R,3aS,6aR) 21 B

free base/(3R,3aS,6aR) 22 B —NH—(CH₂)₃—N(CH₃)₂ free base/(3R,3aS,6aR) 23B —NH—(CH₂)₂—NH(CH₃) free base/(3R,3aS,6aR) 24 B

free base/(3R,3aS,6aR) 25 B

free base/(3R,3aS,6aR) 26 B

free base/(3R,3aS,6aR) 27 C

free base/(3R,3aS,6aR) 28 B

free base/(3R,3aS,6aR)

[0261] TABLE 2

Co. Salt/stereochemistry of No. Scheme R_(a) R_(b) bicyclic ring 29 A—(CH₂)₂—NH—(2-pyridinyl) —N—CO—CH₃ free base/ (3R,3aS,6aR) +(3S,3aR,6aS)

[0262] TABLE 3

Co. Salt/stereochemistry in No. Scheme R_(a) R_(b) R_(a) group 30 D

free base/— 31 A

—N(CH₃)—CO—CH₃ free base/— 32 A

—N(CH₃)—CO—CH₃ trifluoroacetate (1:1)/— 33 A

—N(CH₃)—CO—CH₃ free base/ (3R,3aS,6aR) + (3S,3aR,6aS)

[0263] TABLE 4

Co. Salt/stereochemistry in No. Scheme R_(a) R_(b) R_(a) group 34 D

—NH—CO—CH₂—N(CH₃)₂ free base/3S 35 D

free base/3S 36 D

—NH—CO—CH₂—N(CH₃)₂ free base/3S 37 E

free base/— 38 B

—NH—(CH₂)₂—N(CH₃)₂ free base/— 39 B

—NH—(CH₂)₂—N(CH₃)₂ free base/— 40 B

—NH—(CH₂)₂—N(CH₃)₂ free base/— 41 B

free base/— 42 D

free base/— 43 D

—NH—CO—CH₂—N(CH₃)₂ free base/— 44 B

—NH—(CH₂)₂—N(CH₃)₂ free base/± trans 45 B

free base/— 46 B

free base/— 47 B

trifluoroacetate (1:1)/— 48 B

—NH—(CH₂)₂—N(CH₃)₂ free base/— 49 B

free base/— 50 B

trifluoroacetate (1:1)/— 51 B

—NH—(CH₂)₃—N(CH₃)₂ free base/— 52 B

—NH—(CH₂)₃—N(CH₃)₂ free base/— 53 B

—NH—(CH₂)₃—N(CH₃)₂ free base/— 54 B

—NH—(CH₂)₃—N(CH₃)₂ free base/— 55 B H

free base/— 56 B

—NH—(CH₂)₂—N(CH₃)₂ free base/3S 57 B

free base/— 58 B

free base/— 59 B

free base/— 60 B

free base/— 61 D

free base/— 62 D

free base/— 63 B

free base/3S 64 B

Trifluoroacetate (1:1)/3S 65 B

free base/— 66 B

Trifluoroacetate (1:1)/— 67 B

free base/3S 68 B

Trifluoroacetate (1:1)/3S 69 B

free base/— 70 E

free base/— 71 B

free base/— 72 A

—NH—CO—CH₃ free base/— 73 A

—NH—CO—CH₃ free base/— 74 A

—NH—CO—CH₃ free base/— 75 E

free base/— 76 A

free base/— 77 A

—N(CH₃)—CO—CH₃ free base/— 78 B

free base/— 79 A

—N(CH₃)—CO—CH₃ free base/3S 80 A

—N(CH₃)—CO—CH₃ free base/— 81 A

—N(CH₃)—CO—CH₃ free base/— 82 A

—N(CH₃)—CO—CH₃ free base/— 83 A

—N(CH₃)—CO—CH₃ free base/— 84 A

—NH—CO—CH₃ free base/—

[0264] TABLE 5 Co Structure 04

16

(1-Benzyl-3-{[2-(2-dimethylamino-ethylamino)-benzothiazole-6-sulfonyl]-isobutyl-amino}-2-hydroxy-propyl)- carbamic acidhexahydro-furo[2,3-b] furan-3-yl ester 90

(1-Benzyl-3-{[2-(2-dimethylamino-ethylamino)-benzothiazole-6-sulfonyl]-isobutyl-amino}-2-hydroxy-propyl)- carbamic acidtetrahydro-furan-3-yl ester 20

1-Benzyl-2-hydroxy-3-{isobutyl-[2-(2-pyrrolidin-1-yl-ethylamino)-benzothiazole-6-sulfonyl]-amino}-propyl)-carbamic acidhexahydro-furo[2,3-b] furan-3-yl ester 88

[1-Benzyl-3-({2-[(3-dimethylamino-propyl)-methyl-amino]-benzothiazole-6-sulfonyl}-isobutyl-amino)-2-hydroxy- propyl]-carbamicacid hexahydro-furo[2,3-b] furan-3-yl ester 93

[1-Benzyl-3-({2-[(1-ethyl-pyrrolidin-2-ylmethyl)-amino]-benzothiazole-6-sulfonyl}-isobutyl-amino)-2-hydroxy-propyl]-carbamic acidhexahydro-furo[2,3-b] furan-3-yl ester 87

N′-[(3-fluorophenyl)methyl]glycyl-N-[(1S,2R)-2-hydroxy-3-[[[2-[N-methyl,N-(2-morpholin-4-ylethyl)amino]benzothiazol-6-yl]sulfonyl](2-methylpropyl)amino]-1-(phenylmethyl)propyl]-3-methyl-L-Valinamide, bis-trifluoroacetate 86

N′-[(3-fluorophenyl)methyl]glycyl-N-[(1S,2R)-2-hydroxy-3-[[[2-[3-(dimethylamino)propylamino]benzothiazol-6-yl]sulfonyl](2-methylpropyl)amino]-1-(phenylmethyl)propyl]-3- methyl-L-Valinamide,bis-trifluoroacetate 85

N′-[(3-fluorophenyl)methyl]glycyl-N-[(1S,2R)-2-hydroxy-3-[(2-methylpropyl)[[2-[2-(pyrrolidin-1-yl)ethylamino]benzothiazol-6-yl]sulfonyl]amino]-1-(phenylmethyl)propyl]-3- methyl-L-Valinamide,bis-trifluoroacetate

[0265] TABLE 6 The following compounds were also prepared. The compoundswere evaluated according to the methods described infra. Column 3displays the results as pEC50 against wild type virus (IIIB). Column 4displays the results as pEC50 against wild virus strain F (R13025).Column 5 displays the results as pEC50 against wild virus strain S(R13080). HIV-AVE- HIV-AVE-MT4- MT4-MTT- HIV-AVE-MT4- CompoundMTT-IIIB-2- R13025-2- MTT-R13080-2- number Structure 002 pEC50 002 pEC50002 pEC50 100

8.88 7.36 7.15 101

6.62 102

7.92 6.88 6.02 103

7.7 6.76 6.28 104

7.18 105

7.33 7.25 6.32 106

7.96 7.26 6.66 107

8.7 6.8 6.18 108

7.61 6.54 6.09 109

5.68 5.38 110

8.09 6.17 5.81 111

7.61 6.63 6.18 112

8 6.91 6.82 113

8.29 7.61 7.36 114

7.69 7.47 6.85 115

6.12 5.21 5 116

7.5 7.49 7.36 117

7.32 7.45 6.72 118

6.52 119

6.48 120

6.5 121

7.68 5.55 5 122

5.92 123

5.8 124

5.7 125

8.2 7.57 6.84 126

7.31 5.5 5 127

7.78 7.5 6.87 128

8.23 7.72 7.25 129

7.2 130

7.23 131

7.33 6.08 5.98 132

7.19 133

7.67 7.47 6.8 134

7.21 135

7.18 136

6.14 137

5.77 138

5.84 139

5.68 5.51 5 140

8.34 8.12 141

7.83 6.49 6.02 142

5.25 143

7.13 5 5 144

0 145

7.9 7.4 6.84 146

8.02 6.52 6 147

6.47 148 6.43 6.51 6.56 149

7.29 150

7.37 6.79 6.18 151

6.97 6.09 5.57 152

7.48 6.25 5.76 153

8.13 7.34 6.47 154

8.26 7.42 6.43 155

7.37 7.61 7.49 156

8.14 8.27 7.56 157

7.54 7.5 6.85 158

8.48 8.1 7.52 159

8.1 7.78 7.46 160

7.29 6.32 5.61 161

8.04 7.76 7.47 162

7.69 7.33 6.8 163

7.94 7.31 6.67 164

8.15 7.47 6.8 165

7.35 6.91 6.2 166

8.2 7.66 7.13 167

8.31 7.51 6.85 168

7.61 7.5 6.87 169

8.07 8.17 7.45 170

8.12 7.76 6.79 171

7.29 6.73 6.07 172

7.37 6.61 6.09 173

8.25 7.52 6.81 174

8.04 6.88 6.18 175

7.3 6.03 5.5 176

8.39 7.2 6.65 177

7.43 8.12 7.31 178

7.76 7.97 7.47 179

8.05 7.24 7.32 180

6.81 6.05 5 181

7.48 6.28 5.74 182

8.32 7.44 6.77 183

8.45 8.77 8.15 184

7.76 8.35 7.57 185

7.34 7.48 7.46 85

7.24 186

8.21 8.18 7.54 86

187

188

6.7 7.03 6.88 189

7.35 6.99 6.86

[0266] Antiviral Analyses:

[0267] The compounds of the present invention were examined foranti-viral activity in a cellular assay. The assay demonstrated thatthese compounds exhibited potent anti-HIV activity against a wild typelaboratory HIV strain (HIV-1 strain LAI). The cellular assay wasperformed according to the following procedure.

[0268] Cellular Assay Experimental Method:

[0269] HIV- or mock-infected MT4 cells were incubated for five days inthe presence of various concentrations of the inhibitor. At the end ofthe incubation period, all HIV-infected cells have been killed by thereplicating virus in the control cultures in the absence of anyinhibitor. Cell viability is measured by measuring the concentration ofMTT, a yellow, water soluble tetrazolium dye that is converted to apurple, water insoluble formazan in the mitochondria of living cellsonly. Upon solubilization of the resulting formazan crystals withisopropanol, the absorbance of the solution is monitored at 540 nm. Thevalues correlate directly to the number of living cells remaining in theculture at the completion of the five day incubation. The inhibitoryactivity of the compound was monitored on the virus-infected cells andwas expressed as EC₅₀ and EC₉₀. These values represent the amount of thecompound required to protect 50% and 90%, respectively, of the cellsfrom the cytopathogenic effect of the virus. The toxicity of thecompound was measured on the mock-infected cells and was expressed asCC₅₀, which represents the concentration of compound required to inhibitthe growth of the cells by 50%. The selectivity index (SI) (ratioCC₅₀/EC₅₀) is an indication of the selectivity of the anti-HIV activityof the inhibitor.

[0270] The compounds 1-4, 7, 9-19, 21, 24-26, 28, 33-35, 37-43, 45, 46,49, 50, 56, 61-64, 66, 68, 70, 71, 75, 79-83 and 88-93 all have an EC₅₀value against HIV-1 strain LAI of less than 50 nM. The SI for thesecompounds ranges between about 400 up to more than 47000.

[0271] The compounds 5, 6, 20, 22, 23, 29, 36, 44, 47, 48, 51-55, 58,59, 69, 72-74, 76-78 and 84 all had an EC₅₀ value against HIV-1 strainLAI between 50 nM and 500 nM. The SI for these compounds ranges betweenabout 26 up to more than 1900.

[0272] The compounds 27, 30, 31, 57 and 60 have an EC₅₀ against HIV-1strain LAI of more than 500 nM. The SI for these compounds rangesbetween more than 13 up to more than 183.

[0273] Antiviral Spectrum:

[0274] Because of the increasing emergence of drug resistant HIVstrains, the present compounds were tested for their potency againstclinically isolated HIV strains harboring several mutations. Thesemutations are associated with resistance to protease inhibitors andresult in viruses that show various degrees of phenotypiccross-resistance to the currently commercially available drugs such asfor instance saquinavir, ritonavir, nelfinavir, indinavir andamprenavir.

[0275] Results:

[0276] As a measure of the broad spectrum activity of the presentcompounds, the fold resistance (FR) defined as FR=EC₅₀(mutantstrain)/EC₅₀(HIV-1 strain LAI). Table 7 shows the results of theantiviral testing in terms of fold resistance. As can be seen in thistable, the present compounds are effective in inhibiting a broad rangeof mutant strains. TABLE 7 STRAIN Co LAI A B C D E F G H I J K L M N O PQ R S T 1 1 0.4 0.3 0.7 0.7 0.6 0.8 0.3 0.9 0.8 0.5 0.4 0.2 0.5 1.0 0.40.2 0.8 0.7 1.0 5.1 2 1 0.3 0.2 0.2 0.3 0.4 1.1 0.2 1.0 0.7 0.4 0.2 0.20.3 1.1 0.8 0.2 0.3 0.3 1.7 29.6 3 1 0.4 0.4 0.4 0.8 0.4 1.1 0.4 1.0 0.80.4 0.4 0.3 0.4 2.3 1.0 0.4 0.5 0.5 1.8 34.2 4 1 — — — — — 2.2 — 1.9 1.20.5 — — — — 0.5 — — — 2.9 48.8 5 1 — — — — — 0.5 — 0.6 0.6 0.3 — — — —0.4 — — — 0.6 2.6 6 1 — — — — — 24.0 — 7.7 5.3 5.6 — — — — 4.7 — — —30.7 104.3 7 1 0.2 0.3 0.5 0.5 0.3 0.5 0.2 0.5 0.5 0.4 0.3 0.1 0.1 0.50.4 0.1 0.4 0.4 2.0 12.4 9 1 1.5 1.5 1.6 5.7 2.3 13.0 1.5 6.7 2.3 6.21.0 0.7 0.5 1.5 3.7 0.2 1.8 1.2 29.3 550.9 10 1 0.4 0.4 0.6 0.5 0.4 0.50.5 0.4 0.4 0.3 0.3 0.2 0.3 0.0 0.4 0.3 0.3 0.3 0.5 4.9 11 1 0.3 0.4 0.50.3 — 0.7 0.5 0.9 0.5 0.4 0.4 0.3 0.4 1.6 0.7 0.3 0.0 0.5 1.1 7.3 12 10.3 0.4 0.3 0.4 0.4 0.4 0.2 0.4 0.4 0.3 0.2 0.1 0.2 0.4 0.4 0.1 0.4 0.40.8 5.9 13 1 0.2 0.2 0.2 0.2 0.2 0.6 0.2 0.6 0.3 0.2 0.2 0.1 0.2 1.0 0.30.2 0.4 0.2 1.0 5.8 14 1 0.2 0.2 0.2 0.2 0.3 0.4 0.2 0.5 0.4 0.3 0.2 0.10.2 0.9 0.3 0.2 0.3 0.2 0.7 5.9 15 1 0.3 0.2 0.3 0.3 0.3 0.5 0.3 0.5 0.30.3 0.3 0.1 0.2 0.4 0.2 0.1 0.2 0.2 0.8 7.2 16 1 0.2 0.3 0.2 0.2 0.3 0.40.2 0.3 0.3 0.3 0.2 0.1 0.2 0.4 0.3 0.1 0.2 0.2 1.6 6.6 17 1 — — — — —0.3 — 0.8 0.7 0.2 — — — — 0.3 — — — 0.6 1.0 18 1 — — — — — 1.0 — 1.0 0.90.9 — — — — 0.9 — — — 1.0 5.4 19 1 — — — — — 2.4 — 2.1 1.1 0.6 — — — —0.5 — — — 2.2 10.5 20 1 — — — — — 0.5 — 0.5 0.4 0.2 — — — — 0.2 — — —0.5 2.6 21 1 — — — — — 16.6 — 4.8 3.7 3.3 — — — — 3.4 — — — 38.6 380.022 1 — — — — — 0.3 — 0.4 0.6 0.4 — — — — 0.4 — — — 1.4 6.0 23 1 — — — —— 1.1 — 1.2 1.0 1.0 — — — — 0.9 — — — 1.1 1.2 24 1 — — — — — 16.6 — 4.71.1 4.5 — — — — 1.6 — — — 24.1 174.9 25 1 — — — — — 26.0 — 4.7 3.5 6.0 —— — — 5.6 — — — 42.5 619.8 26 1 — — — — — 29.6 — 20.3 6.6 9.2 — — — —10.6 — — — 34.1 345.6 27 1 — — — — — 1.4 — 1.2 1.3 0.7 — — — — 0.6 — — —5.1 5.4 28 1 — — — — — 2.3 — 1.8 1.4 0.7 — — — — 0.8 — — — 4.4 12.7 30 1— — — — — — — — — — — — — — — — — — — — 31 1 — — — — — — — — — — — — — —— — — — — — 33 1 — — — — — 7.6 — 6.8 7.1 5.9 — — — — 3.4 — — — 467.3467.3 34 1 5.0 5.9 5.5 6.6 4.5 61.9 3.2 11.4 5.6 5.8 1.3 1.2 1.2 4.0 5.00.9 4.0 1.1 99.6 802.7 35 1 0.5 0.9 0.6 0.5 0.9 2.1 0.5 0.8 0.8 0.8 0.40.2 0.6 1.1 0.3 0.2 0.9 0.9 4.3 22.2 36 1 — — — — — 0.2 — 0.6 0.5 0.2 —— — — 0.2 — — — 0.2 0.2 37 1 6.1 1.9 3.8 1.4 1.6 6.1 1.3 4.1 6.8 5.0 0.52.1 5.0 1.4 7.3 0.3 3.8 1.5 10.0 185.8 38 1 — — — — — 12.4 — 2.0 1.1 3.9— — — — 1.2 — — — 11.9 230.4 39 1 — — — — — 19.7 — 2.3 2.4 2.2 — — — —1.7 — — — 16.5 249.9 40 1 — — — — — 7.2 — 2.1 6.4 2.7 — — — — 3.2 — — —12.8 87.8 41 1 — — — — — 44.4 — 2.3 2.5 5.6 — — — — 2.0 — — — 37.6 252.542 1 0.9 0.4 0.9 0.5 0.3 1.2 0.7 0.9 1.9 1.6 0.5 0.6 0.7 1.0 2.1 0.2 1.11.0 2.4 24.5 43 1 1.1 0.9 1.1 0.9 0.7 1.1 0.6 1.3 1.5 3.4 0.4 1.0 1.21.2 2.4 0.2 1.1 1.0 3.0 31.4 44 1 — — — — — 80.2 — 29.4 7.5 29.5 — — — —11.2 — — — 89.3 89.3 45 1 — — — — — 17.3 — 1.2 4.0 1.1 — — — — 1.3 — — —19.9 103.0 46 1 — — — — — 4.7 — 1.3 3.3 2.8 — — — — 3.2 — — — 7.1 44.447 1 — — — — — — — — — — — — — — — — — — — — 48 1 — — — — — 9.4 — 2.52.5 6.5 — — — — 4.3 — — — 13.8 175.0 49 1 — — — — — 12.8 — 3.6 2.9 5.5 —— — — 3.9 — — — 17.8 114.0 50 1 — — — — — 8.6 — 1.4 1.7 7.0 — — — — 3.5— — — 27.9 165.5 51 1 — — — — — 2.9 — 1.8 2.6 0.9 — — — — 0.6 — — — 2.151.8 52 1 — — — — — 10.2 — 1.8 1.3 2.7 — — — — 1.6 — — — 20.3 124.5 53 1— — — — — 2.1 — 0.6 1.3 1.4 — — — — 1.6 — — — 3.8 49.8 54 1 — — — — —3.6 — 0.6 0.9 0.4 — — — — 0.4 — — — 1.8 1.4 55 1 — — — — — 26.2 — 10.09.1 26.2 — — — — 26.2 — — — 26.2 26.2 56 1 — — — — — 33.1 — 4.6 3.2 2.8— — — — 2.1 — — — 67.1 509.6 57 1 — — — — — 1.3 — 1.6 1.3 1.3 — — — —1.3 — — — 1.6 9.0 58 1 — — — — — 2.1 — 1.6 0.7 2.0 — — — — 1.7 — — — 4.427.0 59 1 — — — — — 2.3 — 1.2 1.2 1.7 — — — — 2.0 — — — 4.7 22.2 60 1 —— — — — 1.2 — 1.3 1.3 0.6 — — — — 1.1 — — — 1.4 4.1 61 1 — — — — — 32.7— 5.2 4.8 10.6 — — — — 7.1 — — — 80.0 1090.0 62 1 — — — — — 14.5 — 3.22.8 2.4 — — — — 2.7 — — — 16.1 277.9 63 1 — — — — — — — — — — — — — — —— — — — — 64 1 0.7 0.7 0.6 0.6 0.7 4.6 0.6 0.9 1.3 1.0 0.7 0.2 0.7 0.90.8 0.2 2.3 0.6 17.0 165.5 66 1 — — — — — 4.0 — 0.9 1.0 1.2 — — — — 1.0— — — 5.6 87.9 68 1 — — — — — 65.2 — 7.3 2.4 3.9 — — — — 3.5 — — — 180.7775.2 69 1 — — — — — — — — — — — — — — — — — — — — 70 1 — — — — — 4.7 —3.1 3.7 3.3 — — — — 3.2 — — — 10.4 145.1 71 1 — — — — — 29.6 — 2.7 2.27.0 — — — — 5.0 — — — 79.6 321.5 72 1 — — — — — 67.0 — 24.9 26.2 11.4 —— — — 24.4 — — — 118.0 641.1 73 1 — — — — — 43.1 — 9.8 12.1 14.1 — — — —20.7 — — — 966.6 966.6 74 1 — — — — — — — — — — — — — — — — — — — — 75 1— — — — — 16.3 — 3.6 7.4 19.4 — — — — 18.7 — — — 19.0 93.6 76 1 — — — —— — — — — — — — — — — — — — — — 77 1 — — — — — 8.9 — 2.2 8.3 11.0 — — —— 11.7 — — — 11.6 144.7 78 1 — — — — — 4.8 — 2.6 3.9 2.9 — — — — 8.9 — —— 12.1 60.5 79 1 — — — — — 113.0 — 12.1 3.9 9.8 — — — — 7.4 — — — 313.0893.1 80 1 — — — — — 17.4 — 5.7 3.9 17.6 — — — — 8.1 — — — 26.6 457.6 811 — — — — — 106.8 — 5.6 6.1 29.6 — — — — 20.4 — — — 121.0 387.6 82 1 — —— — — 13.8 — 5.0 4.4 5.5 — — — — 8.0 — — — 17.9 214.1 83 1 — — — — —106.6 — 4.6 7.4 8.4 — — — — 1.5 — — — 132.1 438.6 84 1 — — — — — 54.3 —11.7 13.0 19.6 — — — — 6.1 — — — 195.4 195.4 88 1 8.7 26.3 89 1 21.964.6 90 1 28.8 128.8 91 1 64.6 323.6 92 1 31.6 104.7 93 1 1.1 4.68

[0277] Strain Resistance associated mutations A L10I, K20R, M36I, I54V,A71V, V82T, I84V B L10I, K20R, L24I, M36I, I54V, L63P, A71V, V82T, I84VC L10I, K20R, M36I, M46I, I54V, L63P, A71V, V82T, L90M D L10I, M36I,I54V, L63P, A71V, G73S, I84V, L90M E L10I, K20R, L24I, M36I, M46I, I54V,L63P, A71V, G73S, V82T, I84V, L90M F L10I, M46I, L63P, A71V, I84V GL10I, L24I, M36V, M46I, I54V, L63P, A71V, V82T, I84V H L10I, K20R, M36I,L63P, A71V, G73S, V77I, I84V, L90M I L10I, K20M, I54V, L63P, A71V, I84V,L90M J L10I, M36I, M46I, L63P, A71V, V77I, I84V, N88D, L90M K L10I,M36I, I54V, L63P, A71V, V82T, L90M L L10I, L24I, G48V, I54V, V77I, V82T,L90M M L10I, L24I, M36I, I54V, L63P, V82T, L90M N L10I, M46I, I54V,L63P, A71V, V82A, L90M O L10I, L24I, M36I, I54V, L63P, A71V, I84V PL10I, D30N, L63P, V77I, N88D Q L10I, K20R, I54L, L63P, A71V, G73S, L90MR L10I, M46I, I54V, L63P, A71T, V77I, V82A, L90M S L10F, M46I, L63P,A71V, I84V T V32I, M36I, M46I, I47V, I50V, L63P, L90M U L10F, M46I,I47V, L63P, A71V, I84V

[0278] Biovailability:

[0279] The bioavailability of the present compounds was measured inrats. The compounds were administered orally or intra peritoneal.Animals were sacrificed at different time points after administration,whole blood was collected and serum prepared by standard methods.Concentration of the compound in serum was determined by titrating theanti-HIV activity present in the sample according to the proceduredescribed above. Serum concentrations were also measured by HPLC-MS.

[0280] Protein Binding Analyses:

[0281] Human serum proteins like albumin (HSA) or alpha-1 acidglycoprotein (AAG) are known to bind many drugs, resulting in a possibledecrease in the effectiveness of those compounds. In order to determinewhether the present compounds would be adversely effected by thisbinding, the anti-HIV activity of the compounds was measured in thepresence of human serum, thus evaluating the effect of the binding ofthe protease inhibitors to those proteins.

[0282] Pharmacokinetic Data

[0283] The pharmacokinetic properties of compounds 20, 88 and 90 weretested on rats and dogs. The compounds were evaluated in Whistar rats,source Iffa Credo, weighing approximately 350 g. Before dosing theanimals were fasted overnight (approximately 12 h fasting period). Thecompounds were dissolved in DMSO. The results represented in the tableconcern the results from the oral dosing of the compounds. Blood wassampled at 30 min, 1 h, 2 h, 3 h, no pre-dose sample was taken. Theamount of the compound in the biological sample was determined usingLC-MS. In the table below “or” means oral dosing, “mpk” means mg perkilogram.

[0284] The results are illustrated in Table 8. TABLE 8 C_(max) (ng/ml)C_(3hours) (ng/ml) C_(max) (ng/ml) (or, rat, 10 mpk, (or, rat, 10 mpk,(or, dog, 10 mpk, Compound DMSO) DMSO) DMSO) 20 1425 401 713 88 254 225379 (PEG) 90 893 684 550

[0285] A high plasma level can be observed for these compounds and morespecifically for the compound such as compound 20, which is due to thegood solubility of said compounds in water.

1. A compound having the formula (I)

and N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs,esters and metabolites thereof, wherein R₁ and R₈ are, eachindependently, hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, arylC₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₆alkyl, aryl, Het¹, Het¹C₁₋₆alkyl,Het², Het²C₁₋₆alkyl; R₁ may also be a radical of formula

 wherein R₉, R_(10a) and R_(10b) are, each independently, hydrogen,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl orC₁₋₄alkyl optionally substituted with aryl, Het¹, Het², C₃₋₇cycloalkyl,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, aminosulfonyl, C₁₋₄alkylS(O)_(t), hydroxy,cyano, halogen or amino optionally mono- or disubstituted where thesubstituents are selected from C₁₋₄alkyl, aryl, arylC₁₋₄alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl andHet²C₁₋₄alkyl; whereby R₉, R_(10a) and the carbon atoms to which theyare attached may also form a C₃₋₇cycloalkyl radical; when L is—O—C₁₋₆alkanediyl-C(═O)— or —NR₈—C₁₋₆alkanediyl-C(═O)—, then R₉ may alsobe oxo; R_(11a) is hydrogen, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl,aryl, arylC₁₋₄alkyl, aminocarbonyl optionally mono- or disubstituted,aminoC₁₋₄alkylcarbonyloxy optionally mono- or disubstituted,C₁₋₄alkyloxycarbonyl, aryloxycarbonyl, Het¹oxycarbonyl, Het²oxycarbonyl,aryloxycarbonylC₁₋₄alkyl, arylC₁₋₄alkyloxycarbonyl, C₁₋₄alkylcarbonyl,C₃₋₇cycloalkylcarbonyl, C₃₋₇cycloalkylC₁₋₄alkyloxycarbonyl,C₃₋₇cycloalkylcarbonyloxy, carboxylC₁₋₄alkylcarbonyloxy,C₁₋₄alkylcarbonyloxy, arylC₁₋₄alkylcarbonyloxy, arylcarbonyloxy,aryloxycarbonyloxy, Het¹carbonyl, Het¹carbonyloxy,Het¹C₁₋₄alkyloxycarbonyl, Het²carbonyloxy, Het²C₁₋₄alkylcarbonyloxy,Het²C₁₋₄alkyloxycarbonyloxy or C₁₋₄alkyl optionally substituted witharyl, aryloxy, Het², halogen or hydroxy; wherein the substituents on theamino groups are each independently selected from C₁₋₄alkyl, aryl,arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², HetC₁₋₄alkyl and Het²C₁₋₄alkyl; R_(11b) is hydrogen, C₃₋₇cycloalkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, C₁₋₆alkyloxycarbonyl, Het¹, Het² orC₁₋₄alkyl optionally substituted with halogen, hydroxy,C₁₋₄alkylS(═O)_(t), aryl, C₃₋₇cycloalkyl, Het¹, Het², amino optionallymono- or disubstituted where the substituents are selected fromC₁₋₄alkyl, aryl, arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl,Het¹, Het², Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl;  whereby R_(11b) may belinked to the remainder of the molecule via a sulfonyl group; eachindependently t is zero, 1 or 2; R₂ is hydrogen or C₁₋₆alkyl; L is—C(═O)—, —O—C(═O)—, —NR₈—C(═O)—, —O—C₁₋₆alkanediyl-C(═O)—,—NR₈—C₁₋₆alkanediyl-C(═O)—, —S(═O)₂—, —O—S(═O)₂—, —NR₈—S(═O)₂ wherebyeither the C(═O) group or the S(═O)₂ group is attached to the NR₂moiety; and whereby the alkanediyl moiety is optionally substituted witharyl, arylC₁₋₄alkyl, C₃₋₇Cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹,Het², Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl; R₃ is C₁₋₆alkyl, aryl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, or arylC₁₋₄alkyl; R₄ ishydrogen, C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl orC₁₋₆alkyl optionally substituted with aryl, Het¹, Het², C₃₋₇cycloalkyl,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, aminosulfonyl, C₁₋₄alkylS(═O)_(t), hydroxy,cyano, halogen or amino optionally mono- or disubstituted where thesubstituents are selected from C₁₋₄alkyl, aryl, aryl-C₁₋₄alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl andHet²C₁₋₄alkyl; A is C₁₋₆alkanediyl, —C(═O)—, —C(═S)—, —S(═O)₂—,C₁₋₆alkanediyl-C(═O)—, C₁₋₆alkanediyl-C(═S)— or C₁₋₆alkanediyl-S(═O)₂—;whereby the point of attachment to the nitrogen atom is theC₁₋₆alkanediyl group in those moieties containing said group; R₅ ishydrogen, hydroxy, C₁₋₆alkyl, Het¹C₁₋₆alkyl, Het²C₁₋₆alkyl,aminoC₁₋₆alkyl whereby the amino group may optionally be mono- ordi-substituted with C₁₋₄alkyl; R₆ is C₁₋₆alkyloxy, Het¹, Het¹oxy, Het²,Het²oxy, aryl, aryloxy or amino; and in case —A— is other thanC₁₋₆alkanediyl then R⁶ may also be C₁₋₆alkyl, Het¹C₁₋₄alkyl,Het¹oxyC₁₋₄alkyl, Het²C₁₋₄alkyl, Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl,aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl; whereby each of the amino groups inthe definition of R₆ may optionally be substituted with one or moresubstituents selected from C₁₋₄alkyl, C₁₋₄alkylcarbonyl,C₁₋₄alkyloxycarbonyl, , aryl, arylcarbonyl, aryloxycarbonyl, Het¹, Het²,arylC₁₋₄alkyl, Het¹C₁₋₄alkyl or Het²C₁₋₄alkyl; and R₅ and —A—R⁶ takentogether with the nitrogen atom to which they are attached may also formHet¹ or Het².
 2. A compound according to claim 1, wherein R₁ and R₈ are,each independently, hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, arylC₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₆alkyl, aryl, Het¹, Het¹C₁₋₆alkyl,Het², Het²C₁₋₆alkyl; R₁ may also be a radical of formula

 wherein R₉, R_(10a) and R_(10b) are, each independently, hydrogen,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl orC₁₋₄alkyl optionally substituted with aryl, Het¹, Het², C₃₋₇cycloalkyl,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- ordi(C₁₋₄alkyl)aminocarbonyl, aminosulfonyl, C₁₋₄alkylS(O)_(t), hydroxy,cyano, halogen or amino optionally mono- or disubstituted where thesubstituents are selected from C₁₋₄alkyl, aryl, arylC₁₋₄alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl andHet²C₁₋₄alkyl; whereby R₉, R_(10a) and the carbon atoms to which theyare attached may also form a C₃₋₇cycloalkyl radical; R_(11a) ishydrogen, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, aryl, aminocarbonyloptionally mono- or disubstituted, aminoC₁₋₄alkylcarbonyloxy optionallymono- or disubstituted, C₁₋₄alkyloxycarbonyl, aryloxycarbonyl,Het¹oxycarbonyl, Het²oxycarbonyl, aryloxycarbonylC₁₋₄alkyl,arylC₁₋₄alkyloxycarbonyl, C₁₋₄alkylcarbonyl, C₃₋₇cycloalkylcarbonyl,C₃₋₇cycloalkylC₁₋₄alkyloxycarbonyl, C₃₋₇cycloalkylcarbonyloxy,carboxylC₁₋₄alkylcarbonyloxy, C₁₋₄alkylcarbonyloxy,arylC₁₋₄alkylcarbonyloxy, arylcarbonyloxy, aryloxycarbonyloxy,Het¹carbonyl, Het¹carbonyloxy, Het¹C₁₋₄alkyloxycarbonyl,Het²carbonyloxy, Het²C₁₋₄alkylcarbonyloxy, Het²C₁₋₄alkyloxycarbonyloxyor C₁₋₄alkyl optionally substituted with aryl, aryloxy, Het² or hydroxy;wherein the substituents on the amino groups are each independentlyselected from C₁₋₄alkyl, aryl, arylC₁₋₄alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het², Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl;R_(11b) is hydrogen, C₃₋₇cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl,Het¹, Het² or C₁₋₄alkyl optionally substituted with halogen, hydroxy,C₁₋₄alkylS(═O)_(t), aryl, C₃₋₇cycloalkyl, Het¹, Het², amino optionallymono- or disubstituted where the substituents are selected fromC₁₋₄alkyl, aryl, arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl,Het¹, Het², Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl; whereby R_(11b) may belinked to the remainder of the molecule via a sulfonyl group; eachindependently t is zero, 1 or 2; R₂ is hydrogen or C₁₋₆alkyl; L is—C(═O)—, —O—C(═O)—, —NR₈—C(═O)—, —O—C₁₋₆alkanediyl-C(═O)—,—NR₈—C₁₋₆alkanediyl-C(═O)—, —S(═O)₂—, —O—S(═O)₂—, —NR₈—S(═O)₂ wherebyeither the C(═O) group or the S(═O)₂ group is attached to the NR₂moiety; R₃ is C₁₋₆alkyl, aryl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl,or arylC₁₋₄alkyl; R₄ is hydrogen, C₁₋₄alkyloxycarbonyl, carboxyl,aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl, C₃₋₇cycloalkyl,C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₆alkyl optionally substituted with aryl,Het¹, Het², C₃₋₇cycloalkyl, C₁₋₄alkyloxycarbonyl, carboxyl,aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl, aminosulfonyl,C₁₋₄alkylS(═O)_(t), hydroxy, cyano, halogen or amino optionally mono- ordisubstituted where the substituents are selected from C₁₋₄alkyl, aryl,arylC₁₋₄alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, Het¹, Het²,Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl; A is C₁₋₆alkanediyl, —C(═O)—, —C(═S)—,—S(═O)₂—, C₁ ₆alkanediyl-C(═O)—, C₁₋₆alkanediyl-C(═S)— orC₁₋₆alkanediyl-S(═O)₂—; whereby the point of attachment to the nitrogenatom is the C₁₋₆alkanediyl group in those moieties containing saidgroup; R₅ is hydrogen, hydroxy, C₁₋₆alkyl, Het¹C₁₋₆alkyl, Het²C₁₋₆alkyl,aminoC₁₋₆alkyl whereby the amino group may optionally be mono- ordi-substituted with C₁₋₄alkyl; R₆ is C₁₋₆alkyloxy, Het¹, Het¹oxy, Het²,Het²oxy, aryl, aryloxy or amino; and in case —A— is other thanC₁₋₆alkanediyl then R₆ may also be C₁₋₆alkyl, Het¹C₁₋₄alkyl,Het¹oxyC₁₋₄alkyl, Het²C₁₋₄alkyl, Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl,aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl; whereby each of the amino groups inthe definition of R₆ may optionally be substituted with one or moresubstituents selected from C₁₋₄alkyl, C₁₋₄alkylcarbonyl,C₁₋₄alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het¹, Het²,arylC₁₋₄alkyl, Het¹C₁₋₄alkyl or Het²C₁₋₄alkyl; and R⁵ and —A—R⁶ takentogether with the nitrogen atom to which they are attached may also formHet¹ or Het².
 3. A compound according to any of claims 1 or 2 wherein R₁hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, arylC₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₆alkyl, aryl, Het¹, Het¹C₁₋₆alkyl, Het², Het C₁₋₆alkyl;wherein Het¹ is a saturated or partially unsaturated monocyclicheterocycle having 5 or 6 ring members, which contains one or moreheteroatom ring members selected from nitrogen, oxygen or sulfur andwhich is optionally substituted on one or more carbon atoms.
 4. Acompound according to any of claims 1 to 3 wherein L is—O—C₁₋₆alkanediyl-C(═O)—.
 5. A compound according to any one of claims 1to 3 wherein L is —O—C(═O)—.
 6. A compound according to any one ofclaims 1 to 3 wherein L is —NR₈—C₁₋₆alkanediyl-C(═O)—, whereby thealkanediyl moiety is optionally substituted with, aryl, arylC₁₋₄alkyl,Het¹, Het², Het¹C₁₋₄alkyl and Het²C₁₋₄alkyl.
 7. A compound according toany one of claims 1 to 6 wherein R₁ is Het¹, Het¹C₁₋₆alkyl, Het² orHet²C₁₋₆alkyl.
 8. A compound according to claim 7 wherein R₁ is Het¹ orHet².
 9. A compound according to claim 8 wherein R₁ is Het¹.
 10. Acompound according to claim 9 wherein R₁ ishexahydro-furo[2,3-b]-furanyl.
 11. A compound according to claim 10wherein R₁ is tetrahydrofuranyl.
 12. A compound according to any one ofclaims 1 to 6 wherein L is —O—C₁₋₆alkanediyl-C(═O)— or—NR₈—C₁₋₆alkanediyl-C(═O)— and R₁ is a radical of formula

wherein R₉ is oxo, R_(10a) and R_(10b) are, each independently, hydrogenor C₁₋₄alkyl optionally substituted with aryl, Het¹, Het²,C₁₋₄alkyloxycarbonyl, carboxyl, aminocarbonyl, hydroxy, or aminooptionally mono- or disubstituted where the substituents are selectedfrom C₁₋₄alkyl, R_(11a) is arylC₁₋₄alkyl, or C₁₋₄alkyl optionallysubstituted with aryl or halogen and R_(11b) is hydrogen, orC₁₋₆alkyloxycarbonyl.
 13. A compound according to claim 12 wherein L is—O—C₁₋₆alkanediyl-C(═O)— or —NR₈—C₁₋₆alkanediyl-C(═O)— and R₁ is aradical of formula

wherein R₉ is oxo, R_(10a) and R_(10b) are hydrogen, R_(11a) isarylC₁₋₄alkyl wherein the aryl group is substituted with a halogen andR_(11b) is hydrogen, or C₁₋₆alkyloxycarbonyl.
 14. A compound accordingto claim 13 wherein L is —O—C₁₋₆alkanediyl-C(═O)— or—NR₈—C₁₋₆alkanediyl-C(═O)— and R₁ is a radical of formula

wherein R₉ is oxo, R_(10a) and R_(10b) are hydrogen, R_(11a) ism-fluorobenzyl and R_(11b) is hydrogen, or C₁₋₆alkyloxycarbonyl.
 15. Acompound according to claim 14 wherein L is —O—C₁₋₆alkanediyl-C(═O)— or—NR₈—C₁₋₆alkanediyl-C(═O)— and R₁ is a radical of formula

wherein R₉ is oxo, R_(10a) and R_(10b) are hydrogen, R_(11a) ism-fluorobenzyl and R_(11b) is hydrogen.
 16. A compound according toclaim 14 wherein L is —O—C₁₋₆alkanediyl-C(═O)— or—NR₈—C₁₋₆alkanediyl-C(═O)— and R₁ is a radical of formula

wherein R₉ is oxo, R_(10a) and R_(10b) are hydrogen, R_(11a) ism-fluorobenzyl and R_(11b) is tert-butyloxycarbonyl.
 17. A compoundaccording to any one of claims 1 to 16 wherein R₃ is arylC₁₋₄alkyl. 18.A compound according to claim 17 wherein R₃ is arylCH₂—.
 19. A compoundaccording to claim 18 wherein R₃ is benzyl.
 20. A compound according toany one of claims 1 to 19 wherein R₄ is C₁₋₆alkyl.
 21. A compoundaccording to claim 20 wherein R₄ is butyl.
 23. A compound according toclaim 21 wherein R₄ is isobutyl.
 23. A compound according to any one ofclaims 1 to 22 wherein A is C₁₋₆alkanediyl, —C(═O)— orC₁₋₆alkanediyl-C(═O)—; whereby the point of attachment to the nitrogenatom is the C₁₋₆alkanediyl group in those moieties containing saidgroup; R₅ is hydrogen, C₁₋₆alkyl, Het¹C₁₋₆alkyl, Het²C₁₋₆alkyl,aminoC₁₋₆alkyl whereby the amino group may optionally be mono- ordi-substituted with C₁₋₄alkyl; and in case —A— is —C(═O)— then R₆ isC₁₋₆alkyloxy, Het¹, Het¹oxy or Het²oxy, aryl, Het¹C₁₋₄alkyl,Het¹oxyC₁₋₄alkyl, Het²C₁₋₄alkyl, Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl,aryloxyC₁₋₄alkyl or aminoC₁₋₄alkyl; and in case —A— is C₁₋₆alkanediylthen R⁶ is amino, C₁₋₆alkyloxy, Het¹, Het¹oxy or Het²oxy; and in case—A— is C₁₋₆alkanediyl-C(═O)— then R⁶ is C₁₋₆alkyloxy, Het¹, Het¹oxy orHet²oxy, aryl, C₁₋₆alkyl, Het¹C₁₋₄alkyl, Het¹oxyC₁₋₄alkyl,Het²C₁₋₄alkyl, Het²oxyC₁₋₄alkyl, arylC₁₋₄alkyl, aryloxyC₁₋₄alkyl oraminoC₁₋₄alkyl; whereby each of the amino groups in the definition of R₆may optionally be substituted with one or more substituents selectedfrom C₁₋₄alkyl, C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl, aryl,arylcarbonyl, aryloxycarbonyl, Het¹, Het², arylC₁₋₄alkyl, Het¹C₁4alkylor Het²C₁₋₄alkyl; and R⁵ and —A—R⁶ taken together with the nitrogen atomto which they are attached may also form Het¹ whereby Het¹ issubstituted by at least an oxo group.
 24. A compound according to claim23 wherein R₅ is hydrogen or C₁₋₆alkyl.
 25. A compound according toclaim 24 wherein R₅ is hydrogen.
 26. A compound according to claim 24wherein R₅ is methyl or ethyl.
 27. A compound according to claim 26wherein R₅ is methyl.
 28. A compound according to claim 23 wherein A isC₁₋₆alkanediyl.
 29. A compound according to claim 28 wherein A isethylenediyl.
 30. A compound according to any one of claims 1 to 29wherein R₆ is a Het¹.
 31. A compound according to claim 30 wherein R₆ isa Het C₁₋₄alkyl.
 32. A compound according to claim 30 wherein R₆ is apyrrolidinyl or pyrrolidinylC₁₋₄alkyl.
 33. A compound according to claim32 wherein R₆ is a pyrrolidinylethyl.
 34. A compound according to anyone of claims 1 to 29 wherein R₆ is an amino; whereby each of the aminogroups may optionally be substituted with one or more substituentsselected from C₁₋₄alkyl, C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl, aryl,arylcarbonyl, aryloxycarbonyl, Het¹, Het², arylC₁₋₄alkyl, Het¹C₁₋₄alkylor Het²C₁₋₄alkyl.
 35. A compound according to claim 34 wherein R₆ is anamino; whereby each of the amino group is substituted with twosubstituents selected from C₁₋₄alkyl.
 36. A compound according to claim35 wherein R₆ is dimethylamino.
 37. A compound according to claim 1having the formula(1-Benzyl-3-{[2-(2-dimethylamino-ethylamino)-benzothiazole-6-sulfonyl]-isobutylamino}-2-hydroxy-propyl)-carbamicacid hexahydro-furo[2,3-b]furan-3-yl ester,(1-Benzyl-3-{[2-(2-dimethylamino-ethylamino)-benzothiazole-6-sulfonyl]-isobutylamino}-2-hydroxy-propyl)-carbamicacid tetrahydro-furan-3-yl ester,1-Benzyl-2-hydroxy-3-{isobutyl-[2-(2-pyrrolidin-1-yl-ethylamino)-benzothiazole-6-sulfonyl]-amino}-propyl)-carbamicacid hexahydro-furo[2,3-b]furan-3-yl ester,[1-Benzyl-3-({2-[(3-dimethylamino-propyl)-methyl-amino]-benzothiazole-6-sulfonyl}-isobutyl-amino)-2-hydroxy-propyl]-carbamicacid hexahydro-furo[2,3-b]furan-3-yl ester,[1-Benzyl-3-({2-[(1-ethyl-pyrrolidin-2-ylmethyl)-amino]-benzothiazole-6-sulfonyl}-isobutyl-amino)-2-hydroxy-propyl]-carbamicacid hexahydro-furo[2,3-b]furan-3-yl ester.
 38. Method for thepreparation of a compound according to claim 1 according to the scheme G

comprising the steps of a) reacting benzothiazole derivative g-1 withchlorosulfonic acid, and subsequently with thionylchloride to yieldintermediate g-2, b) reacting said intermediate g-2 with intermediateg-3 yielding an intermediate g-4 wherein PG is a protecting group, c)reacting intermediate g-4 into intermediates g-5 and g-6, d)intermediates g-5 and g-6 are derivatized with a compound of formulaHN(R₅)A—R₆ yielding and subsequently deprotected yielding intermediateg-7, e) g-7 may then be reacted with an intermediate of formulaR₁—L-(leaving group) resulting in the compound g-8.
 39. A methodaccording to claim 38 wherein the protecting group is Boc.
 40. A methodaccording to any one of claims 38 or 39 wherein step (c) is performedwith a suitable reagent selected from the group comprisingmeta-chloroperoxybenzoic acid or magnesium monoperoxyphtalatehexahydrate.
 41. A pharmaceutical composition, comprising an effectiveamount of at least one compound as claimed in any one of claims 1 to 37,and a pharmaceutically tolerable excipient.
 42. A method of inhibiting aprotease of a multi-drug resistant retrovirus in a mammal infected withsaid retrovirus, comprising administering a protease inhibiting amountof a compound according to any one of claims 1 to 37 to said mammal inneed thereof.
 43. A method of treating or combating infection or diseaseassociated with multi-drug resistant retrovirus infection in a mammal,comprising administering an effective amount of at least one compoundaccording to any one of claims 1 to 37 to said mammal.
 44. A method ofinhibiting multi-drug resistant retroviral replication, comprisingcontacting a retrovirus with an effective amount of at least onecompound according to any one of claims 1 to
 37. 45. The method asclaimed in claim 42, 43 or 44 wherein the retrovirus is a humanimmunodeficiency virus (HIV).
 46. A compound as claimed in any one ofclaims 1 to 37 for use as a medicine.
 47. The use of a compound asclaimed in any one of claims 1 to 37 in the manufacture of a medicamentfor treating or combating infection or disease associated withmulti-drug resistant retrovirus infection in a mammal.
 48. The use of acompound as claimed in any one of claims 1 to 37 in the manufacture of amedicament for inhibiting a protease of a multi-drug resistantretrovirus in a mammal infected with said retrovirus.
 49. The use of acompound as claimed in any one of claims 1 to 37 in the manufacture of amedicament for inhibiting multi-drug resistant retroviral replication.50. The use according to any one of claims 47 to 49 wherein theretrovirus is a human immunodeficiency virus (HIV).
 51. A compoundaccording to claim 1 wherein the compound is listed in table 8.